The Discovery and Function of Filaggrin: Comparison
View Latest Version
Please note this is a comparison between Version 2 by Yvaine Wei and Version 3 by Yvaine Wei.

Keratohyalin granules were discovered in the mid-19th century in cells that terminally differentiate to form the outer, cornified layer of the epidermis.  The first indications of the composition of these structures emerged in the 1960’s from a histochemical stain for histidine, followed by radioauto-graphic evidence for a high incidence of histidine incorporation into newly synthesized proteins in cells containing the granules.  Research during the next three decades revealed the structure and function of the major protein in these granules, which was initially called the ‘histidine-rich pro-tein.’  Steinert and Dale named the protein ‘filaggrin’ in 1981 because of its ability to aggregate keratin intermediate filaments.  The human gene for the precursor ‘profilaggrin’ was reported in 1991 to encode 10, 11 or 12 nearly identical repeats.  Remarkably, the mouse and rat genes encode up to 20 repeats.  The lifetime of filaggrin is the time required for keratinocytes in the granular layer to move into the inner cornified layer.  During this transition, filaggrin facilitates the collapse of corneocytes into an impermeable surface barrier.  The subsequent degradation of filaggrin is as remarkable as its synthesis and the end-products aide in maintaining moisture in the cornified layer.  It became apparent that ichthyosis vulgaris and atopic dermatitis were associated with the absence of this protein.  McLean’s team in 2006 identified the cause of these diseases by discov-ering loss-of-function mutations in the profilaggrin gene that led to dysfunction of the epidermal surface barrier.  This story illustrates the complexity in maintaining a healthy, functional surface barrier.

  • keratohyalin granules
  • histidine-rich protein
  • filaggrin
  • profilaggrin
  • ichthyosis vulgaris
  • atopic dermatitis
  • corneodesmosomes
  • transglutaminase

1. Keratohyalin Granules and Histidine

Karen Holbrook [1] commented that “morphology is often the starting point of an investigation.”  Developments in microscopy during the 19th century opened morphology of the cellular world to full view.  The ability to thin-section fixed tissues and innovations in selectively staining cellular components provided biologists with opportunities to study structures of tissues and the organelles within cells.  Several striking observations made by histochemical and radioautographic analyses of the epidermis were found, which led to the discovery of filaggrin and its short-lived but essential functions in assembly of a healthy surface barrier.

A fascinating morphological feature forms under the cornified layer of the epidermis (Figure 1) as keratinocytes move outward from the proliferative basal layer and terminally differentiate into corneocytes that form the surface barrier of the skin.  Stephen Rothman [2], recounting the early history of studies on these ‘keratohyalin granules,’ remarked that during those slower years of “wax candles and horse carriages,” there was time for “detailed and precise observations that revealed the existence of granules in the granular layer, [which were] first observed and recorded by Auffhammer (1869).”  The granules were further studied by Langerhans (1873) and designated ‘keratohyalin’ in 1882 by Waldeyer.  Although very active in research on the skin throughout his career, Rothman commented shortly before he died in 1963 that not much more had been learned since those early days [3].  He did not live to see the dramatic developments emerging from the investigations of these unusual structures that were already underway in several laboratories.

Seminal observations were published in the years following 1960.  Reaven and Cox [4][5] traced the accumulation of zinc in the granular layer to chelation by the high density of histidine in the keratohyalin granules [6].  The granules stained an intense red color with diazotized sulfanilic acid under alkaline conditions, a coupling reaction developed by Pauly [7] for histidine (Figure 2A).  Kimie Fukuyama, while a visiting scientist in I. A. Bernstein’s laboratory at the University of Michigan, began investigations of the epidermis by the incorporation of radiolabeled nucleotides into DNA and then into RNA by radioautography.  She observed that, whereas DNA was synthesized only in the basal layer, incorporation of precursors into RNA occurred throughout the layers below the stratum corneum [8][9], which suggested that proteins were also synthesized in the outer layers.  The surprise came when she turned to the incorporation of [3H]-amino acids.  As expected, labeled phenylalanine, leucine and methionine were extensively incorporated into the dividing cells of the basal layer but minimally in the outer layers.  Conversely, [3H]histidine and [3H]glycine were preferentially incorporated into the granular layer (Figure 2B) [10][11][12].  The possibility of synthesis of a unique protein exclusively in the granular layer while the cells are undergoing terminal differentiation was proposed by Bernstein, who had become interested in the epidermis as a tissue to study the process of differentiation [13].  This hypothesis called for a deeper analysis, which could only be resolved by purification of a protein enriched in histidine and glycine.

Ijms 23 01455 g001 550

Figure 1. A sketch of the epidermis of the newborn rat [14].
Ijms 23 01455 g002
Figure 2. (A) Human skin stained with the Pauly reagent for histidine [5]. (B) Light microscopic radioautograph of newborn rat epidermis 15 min after intraperitoneal injection of [3H]histidine [11][12].

2. Discovery of the ‘Histidine-Rich’ Protein

This goal was accomplished in Bernstein’s laboratory by one of the authors (JKH) while a graduate student. A protein fraction was extracted from isolated epidermis of newborn rats that contained several-fold more histidine, and a five- to six-fold greater specific radioactivity from injected [3H]histidine or [3H]glycine, than the remaining bulk protein [15][16]. Subsequent graduate students and postdoctoral fellows continued to refine the study of this protein fraction, which became known as the ‘histidine-rich protein (HRP)’ and was definitively localized to the granular layer by dissociation of the lower layers of the epidermis with tetraphenylboron [17]. Extraction of the granular and cornified layers with 8 M urea, dialysis, lyophilization and extraction of the dried material with 0.1 N perchloric acid followed by precipitation at pH 4.5 (the protocol developed by Hoober [14]) yielded a basic protein fraction that contained 7% histidine, 12% arginine, 16% serine and 14% glycine [16][17][18]. The puzzling observation that 8 M urea was required for extraction of a protein inherently water soluble because of the high content of polar amino acids would become clear many years later. Ball et al. [19] prepared a high molecular weight HRP from the granular layer that was converted to a smaller form in the stratum corneum, with kinetics of an apparent precursor/product relationship. Ugel [20][21] extracted proteins from bovine hoof epidermis with 1 M potassium phosphate, pH 7.0, which when dialyzed formed aggregates similar to keratohyalin granules. Application of this technique to newborn rat epidermis generated keratohyalin granule-like structures that contained HRP, thereby providing definite evidence for localization of this protein in the granules [22]. Electrophoresis of proteins in the granules revealed a main fraction with a mass of 46.5 kDa. In a study of mouse epidermis, Balmain et al. [23] found that histidine-rich proteins with a range of 70 kDa to 120 kDa were rapidly synthesized in vitro, whereas a 27 kDa protein appeared simultaneously with the production of mature keratohyalin granules in fetal epidermis [24]. Interestingly, the high concentration of histidine detected by the Pauly reaction did not persist as the cells moved into the cornified layer [4][5][17]. Likewise, [3H]histidine that was incorporated into proteins that were synthesized in the granular layer was lost as the cells moved outward [11][19], which suggested that the protein was degraded to soluble products.
The biochemical work on keratohyalin granules that began in Bernstein’s laboratory had revealed the unusual composition of HRP, and, combined with the unconventional protocol for purification of the protein, initiated a path of research that led to characterization of a “remarkable” protein, as described by Brown and McLean [25]. Beverly Dale introduced purification of epidermal proteins by ion-exchange chromatography in 4 M urea, with which she obtained a ‘basic protein’ with properties similar to HRP [26]. Steinert, Dale and their colleagues [27] succeeded in further purifying the protein to homogeneity in 8 M urea, with final steps in dilute formic acid, from newborn mouse and rat epidermis. The mouse and rat proteins were estimated by gel electrophoresis to have masses of 30 kDa and 48 kDa, respectively. However, equilibrium sedimentation in 6 M guanidine hydrochloride yielded masses of 25.8 kDa and 38.4 kDa, respectively. The purified basic proteins, with a pI greater than pH 9.5 [26][27][28], contained about 8% histidine and 12 or 14% arginine, but little, if any, lysine, valine, leucine, tyrosine, phenylalanine or tryptophan and no cysteine or methionine. Peter Steinert and colleagues had extensively studied the intermediate filaments of keratin [29]. When these filaments were prepared from subunits purified from mouse, bovine and hamster tissues and mixed with HRP purified from mouse stratum corneum, a rapid increase in turbidity occurred with formation of macrofibrils. Analysis of these complexes revealed 2 mol of HRP per 3 mol of keratin intermediate filament subunits. Control experiments showed that the basic protein did not interact specifically with F-actin or tubulin. These findings were the first demonstration of the function of HRP, and Steinert, Dale, and their colleagues bestowed upon the protein the name ‘filaggrin’ (fil-ăg’-grin) for its ability to aggregate keratin intermediate filaments [27]. In contrast to filaggrin, keratin is synthesized in cells of the basal and spinous layers and becomes the bulk of the protein content in corneocytes [30].

3. The Precursor, Profilaggrin

In 1989, Steinert’s research team at the National Institutes of Health, in collaboration with Bernstein at the University of Michigan, Croce at Temple University, Parry at Massey University and Lessin at the University of Pennsylvania, published the partial structure of the human profilaggrin gene, which contained 12 repeating units [31]. The nucleotide and deduced amino acid sequences showed that each repeat contains 324 amino acids, with considerable sequence variation among the repeats. Each repeat of the human protein is separated by a conserved linker of seven amino acids with the sequence FLYQVST [31], whereas the rat and mouse profilaggrins have linkers that contain the sequence VYYY [32]. Cleavage of the protein and trimming of the linker provide filaggrin monomers with 317 amino acids and a mass of 37 kDa. Figure 3 illustrates the structure of the human profilaggrin gene. Ijms 23 01455 g003
Figure 3. The human profilaggrin gene on chromosome 1q21. Exon 2 contains the translation initiation codon. The entire coding region of the protein is within the uninterrupted exon 3.
Remarkably, the mouse [33] and rat [34] profilaggrin genes were found to contain 20 repeats. Nearly equal amounts of two different, randomly arranged repeats, 250 and 255 amino acids in length, occur in the mouse protein, and are separated by short linker sequences. The mouse and rat proteins have 60% homology between the sequences [35], but both have less sequence homology with the human protein. 

4. The Short Life of Filaggrin

Upon synthesis, profilaggrin is heavily phosphorylated and is incorporated into keratohyalin granules. As cells of the granular layer move through the transitional zone into the inner layers of the cornified layer, the protein is dephosphorylated, and a complex group of proteases cleaves the precursor into monomeric filaggrin, which binds to keratin intermediate filaments and causes collapse of the cytoplasm into the predominant component of the flattened corneocytes [27][36]. As the cells move outward, only the first few inner layers of the cornified layer contain filaggrin, whereas the outer layers retain keratin [37]. The absence of histidine by histochemical analysis and [3H] from labeled histidine in the outer cornified layers revealed that filaggrin is degraded as corneocytes proceed through the inner layers of the stratum corneum.
A flowchart that illustrates the steps in this process is provided in Figure 4 (see legend for reference numbers). The N-terminal A domain, which contains the Ca2+-binding EF-hand sequences, is cleaved from profilaggrin prior to processing of the remainder of the protein. Skin-specific retrovirus-like aspartic protease (SASPase) cleaves the linker sequences to yield active monomers that bind to keratin intermediate filaments. Knock-out of the serine proteases CAP1/Prss8 and matriptase/MT-SP1 caused incomplete processing of profilaggrin and little, if any, monomeric filaggrin, which suggested that these proteases are also involved in processing profilaggrin to the monomeric form. Upon completing its function in facilitating collapse of keratin filaments, filaggrin is further degraded by calpain 1, caspase 14 and bleomycin hydrolase to free amino acids (Figure 4B). The final mixture of amino acids, along with urocanic acid (UCA) produced by deamination of histidine, 2-pyrrolidone carboxylic acid (PCA) produced by cyclization of glutamine and other metabolic products, have been designated the ‘natural moisturizing factor (NMF)’ and aid in maintaining hydration of the stratum corneum. The activity of most of these proteases is Ca2+-dependent.
Ijms 23 01455 g004
Figure 4. Flowchart of the processing of profilaggrin to free amino acids. (A). Proflaggrin to filaggrin. (1) Phospho-profilaggrin is dephosphorylated by phosphatases. (2) The A (yellow) and B (green) domains are cleaved from profilaggrin by furin, PACE4 (Paired basic Amino acid Cleaving Enzyme 4) and endoproteinase-1 (PEP1) [38][39][50,51]. (3) Linker sequences of human profilaggrin (FLYQVST) are cleaved by skin-specific retrovirus-like aspartic protease (SASPase) [40][52], channel-activating serine protease (CAP1) [41][53] and matriptase (MT-SP1) [42][54] to monomeric filaggrin. Aminopeptidases and carboxypeptidases are likely involved in trimming the new termini [32][37]. (B). Filaggrin to NMF. (4) Arginine residues in filaggrin and keratin are converted to citrulline by peptidylarginine deiminase (PAD1 or 3) [37][43][49,55]. Deiminated filaggrin is cleaved by calpain-1 and caspase-14 (at VSQD and HSED sequences) to filaggrin fragments [43][44][45][55,56,57]. (5) Filaggrin fragments are digested by neutral cysteine protease (bleomycin hydrolase) to amino acids [45][57]. Aminopeptidases and carboxypeptidases are also likely involved. (6) Histidine is converted by histidine deaminase to trans-urocanic acid (UCA), which has a UV spectrum similar to that of nucleic acids and proteins [46][58] and provides a natural sunscreen [47][59]. Glutamine is non-enzymatically converted to 2-pyrrolidone carboxylic acid (PCA). These hydrophilic final products contribute to the moisturizing of the skin [44][45][48[56,57,60,61][49]. Kezic et al. [50][62] and de Veer et al. [51] [63] provided excellent reviews of proteolytic processing of filaggrin and differentiation of corneocytes.

5. Mutations That Cause Loss of Filaggrin

A major discovery published in 2006 revealed the cause of the complete loss of filaggrin in ichthyosis vulgaris and atopic dermatitis (AD), diseases that result from defective formation of the surface barrier [5238]. The loosened cornified layer of the skin in these cases allows water to escape and allergens to gain access to internal cells [5339]. Irwin McLean’s team at the University of Dundee identified mutations in the first repeat in exon 3 of the profilaggrin gene (R501X generates a nonsense stop-codon, and the 2282del4 deletion also results in a stop-codon), thus revealing the genetic cause of these diseases [25][5238][5339][5440]. The null mutations R501X and 2282del4 are prevalent in European and Asian populations and lead to the complete absence of profilaggrin in homozygous individuals. Within the next 5 years, an extensive mutation map was generated that showed significant differences between European and Asian populations (Figure 5). A recent analysis of 126 patients with atopic dermatologic disorders in Saudi Arabia detected 227 variants, including missense, silent, nonsense, frameshift and noncoding mutations in exon 3 of the profilaggrin gene [5541]. 
Ijms 23 01455 g005
Figure 5. Filaggrin mutations among populations. Mutations that are recurrent in European and Asian populations are indicated in red, and rare or family specific mutations are in black. These mutations are either nonsense mutations or out-of-frame insertions or deletions that are predicted to cause loss-of-function. Exon 3 of the gene contains the complete sequence for profilaggrin, shown here with 10 repeats as orange hexagons. The yellow circle is the S-100-like Ca2+-binding domain, the green rectangle is the B domain, and the blue diamonds are incomplete repeats [53] (with permission from A. D. Irvine).-binding domain, the green rectangle is the B domain, and the blue diamonds are incomplete repeats [65] (with permission from A. D. Irvine).
Mutations in the gene encoding profilaggrin are the strongest risk factors for skin diseases. About 50% of AD patients carry loss-of-function mutations in filaggrin [5642]. Esparza-Gordillo et al. [5743] indicated that 10% to 20% of people in industrialized countries suffer from AD (eczema), with a strong disposition in children when the mother carries an  indicated that 10% to 20% of people in industrialized countries suffer from AD (eczema), with a strong disposition in children when the mother carries an FLG mutation. Ichthyosis vulgaris is one of the most common skin diseases, characterized by dry, flaky skin, with a prevalence of at least 1 case per 250 persons. The complexity of these diseases was expanded by Butler et al.  mutation. Ichthyosis vulgaris is one of the most common skin diseases, characterized by dry, flaky skin, with a prevalence of at least 1 case per 250 persons. The complexity of these diseases was expanded by Butler et al. [5844], who identified twelve distinct diseases within the spectrum of AD. AD is an inflammatory condition, often with open lesions, that affects 14% of children in the US [5945] and up to 25% in the UK and Scandinavia [6046]. AD is the most common chronic skin disease in early childhood and peaks at 2 to 3 years of age, after which it declines to a few percent in adults [6046][6147].
Interestingly, defects in processing profilaggrin appear to be more severe than a complete lack of filaggrin. Mice with a deficiency in the protease CAP1 [4148] processed profilaggrin to short oligomers but no further, which resulted in an impaired surface barrier, rapid dehydration and death shortly after birth. Pleotropic effects of a deficiency of matriptase/Mt-SP1 also were related to a defect in processing of profilaggrin during cornification of the epidermis, but the minimal processing in these animals seemed to cause less severe disease [4249].
A healthy skin requires continual loss of the outer layers by corneocyte desquamation; the outer layers are replaced by dividing cells in the basal layer. However, an excessive loss of corneocytes causes an extreme type of lesional disease similar to AD, known as Netherton syndrome (NS), which results in inflammation and allergic reactions [6250][6351]. NS is a life-threatening disorder that affects approximately one in 200,000 newborn children [6250]. This disease is mediated by kallikrein-related serine peptidases (KLKs), whose normal function is to degrade corneodesmosomes and allow detachment of superficial corneocytes. KLK5 and KLK7 are synthesized as zymogens and activated by cleavage of the precursor forms by mesotrypsin and matriptase [6452]. Excessive loss of corneocytes by overactive KLK5 and KLK7 is controlled by the serine protease inhibitor lymphoepithelial Kazai-type-related inhibitor (LEKT1) encoded by the SPINK5 gene. LEKT1 is also degraded by mesotrypsin, which is activated by enteropeptidase in the granular layer [6452]. NS is caused by a loss-of-function mutation in the SPINK5 gene, which allows heightened activity of KLKs. Knock-out of KLK5 reversed NS symptoms in a SPINK5-deficient mouse model [6250][6351][6452][6553]. Because of lethality of the Spink5−/− knock-out, immunological consequences of the mutation were studied in skin grafts on nude mice. Activation of protease-activated receptor 2 (PAR2), a major effector of the inflammatory response, by KLK5 led to recruitment of eosinophilic and mast cells and formation of lesions [6553].

6. Keratinocyte to Corneocyte Transition

The context in which filaggrin functions is the transition of keratinocytes to corneocytes. More specifically, this transition involves formation of the cornified envelope and the conversion of cell cytoplasm to an insoluble matrix. Proteins synthesized in the granular layer are organized into a structure, referred to as the ‘cornified envelope,’ that lines the cytoplasmic surface of the cell membrane [6654][6755][6856][6957]. Transglutaminases catalyze cross-links between these proteins, which are essential for stabilization of the complex. Three isozymes of the Ca2+-dependent transglutaminase family, TGM1, TGM3 and TGM5, are expressed in the epidermis and function within terminally differentiating keratinocytes [6957]. An early step in formation of the cornified envelope is attachment of involucrin to the inner surface of the cell membrane by cross-links catalyzed by the essential enzyme TGM1 [6755][6957]. Although involucrin contains 39 repeats of a 10-amino-acid sequence, with each containing three glutamine (Q) residues, only one in this 585-amino acid protein—within the sequence ELPEQQVGQP (the reactive Q is underlined and bold)—is a substrate for TGM1 in vitro unless the protein is proteolytically degraded [7058]. Loricrin, an abundant protein that comprises about 80% of the cornified envelope, is synthesized in cells of the granular layer and forms oligomers with small, proline-rich proteins [7159][7260]. These complexes are stabilized by TGM3 and then fixed onto the involucrin-containing scaffold by formation of cross-links catalyzed by TGM1 [6654]. The keratin filament-filaggrin complex and several minor proteins, such as elafin, are added sequentially to the inner surface of the cell membrane. Keratin and a small amount of filaggrin are cross-linked to loricrin but not to each other [7260]. Cross-links, mostly to loricrin, stabilize the cornified envelope and generate the insoluble matrix of corneocytes. Mutations in the TGM1 gene cause the skin disorder lamellar ichthyosis, and TGM1−/− knockout mice die within a few hours after birth [6755][7361].
Liedén et al. [7462] and Su et al. [7563]  demonstrated a remarkable increase in expression of these transglutaminases in the epidermis of patients with AD. Whereas TGM1 and TGM3 are intracellular enzymes, repair of damage to the epidermis appears to also require extracellular transglutaminase activity. TGM2 is ubiquitously expressed and, unlike other members of the family, is found in the extracellular space [7664][7765][7866][7967]. Expression of TGM2 is induced in inflamed and wounded tissues [7664][8068][8169][8270][8371] and also by dexamethasone [8472]. TGM2 normally occurs in an inactive, closed conformation but is rapidly converted to the open, active form by injury [8068][8573]. Closure of wounds is significantly impaired in TGM2 knock-out mice [8674], and processes required for wound healing and extracellular matrix remodeling are dramatically reduced when fibroblasts and macrophages are rendered TGM2-deficient by transfection with anti-sense RNA [8068][8169].
Whereas the corneocytes are the “bricks” of the surface barrier, ceramides and other lipids are extruded into the extracellular space to form the “mortar” [8775][8876]. Impermeability to water is provided by the extracellular lipids, as demonstrated by complete abrogation of the permeability barrier by the extraction of lipids [8977][9078]. Points of contact between corneocytes occur at villus-like structures, which at their tip contain corneodesmosomes, a complex consisting of cohesion proteins corneodesmosin, desmoglein 1 and desmocollin 1 [9179][9280]. Corneodesmosin is synthesized in the lower granular layer of the epidermis and is secreted from keratinocytes in vesicles as a glycoprotein [9381][9482]. In healthy skin, corneocytes are tightly stacked in the stratum corneum and express these villus-like structures mostly on their outermost rims (Figure 7B). Riethmüller et al. [9583]  discovered that these structures are approximately five-fold more numerous on homozygous FLG−/− cells than on wild-type cells and cover the entire surface of the loosely packed mutant corneocytes (Figure 7A). The less tightly stacked stratum corneum of FLG−/−  individuals is also characterized by a nearly two-fold increase in TEWL [9583]. Although important for stability of the stratum corneum, corneodesmosomes do not inhibit water flow between cells. However, TEWL could possibly be reduced if adherence of corneocytes in filaggrin-deficient patients was increased. Ijms 23 01455 g007
Figure 7. Corneodesmosomes. (A) Filaggrin-deficient (FLG−/−) corneocytes from tape-stripped stratum corneum of patients with AD express corneodesmosin on villus-like projections that cover the entire cell surface. (B) In contrast, corneocytes from the tightly packed stratum corneum of wild-type (FLG+/+) patients contain corneodesmosin mostly on lateral rims of the cells. The images were prepared by incubating corneocytes with anti-corneodesmosin antibodies followed by immunogold labeling and scanning electron microscopy [95] (with permission from S. Kezic).) patients contain corneodesmosin mostly on lateral rims of the cells. The images were prepared by incubating corneocytes with anti-corneodesmosin antibodies followed by immunogold labeling and scanning electron microscopy [124] (with permission from S. Kezic).
An account of the intensive path of research was provided here, which in a relatively short period of time since its humble beginnings has achieved a level of understanding of cornification of the skin that is making a significant impact on quality of life.

References

  1. Holbrook, K.A. Biologic structure and function: Perspectives on morphologic approaches to the study of the granular layer keratinocyte. J. Investig. Dermatol. 1989, 92, s84–s104.
  2. Rothman, S. Keratinization in historical perspective. In The Epidermis; Montagna, W., Lobitz, W.C., Jr., Eds.; Academic Press: New York, NY, USA, 1964; pp. 1–14.
  3. Burgdorf, W.H.C.; Bickers, D.R. The scientific legacy of Stephen Rothman. J. Investig. Dermatol. 2015, 135, 954–959.
  4. Reaven, E.P.; Cox, A.J., Jr. The histochemical localization of histidine in the human epidermis and its relationship to zinc binding. J. Histochem. Cytochem. 1963, 11, 782–790.
  5. Reaven, E.P.; Cox, A.J. Histidine and keratinization. J. Investig. Dermatol. 1965, 45, 422–431.
  6. Reaven, E.P.; Cox, A.J. Binding of zinc by the transitional layer of the epidermis. J. Investig. Dermatol. 1962, 39, 133–137.
  7. Pauly, H. Über die Konstitution des Histidins. I. Mitteilung. Z. Physiol. Chem. Hoppe-Seyler 1904, 42, 508–518.
  8. Fukuyama, K.; Bernstein, I. Autoradiographic Studies of the Incorporation of Thymidine-H3into Deoxyribonucleic Acid in the Skin of Young Rats1. J. Investig. Dermatol. 1961, 36, 321–326.
  9. Fukuyama, K.; Bernstein, I.A. Site of synthesis of ribonucleic acid in mammalian epidermis. J. Investig. Dermatol. 1963, 41, 47–52.
  10. Fukuyama, K.; Nakamura, T.; Bernstein, I.A. Differentially localized incorporation of amino acids in relation to epidermal keratinization in the newborn rat. Anat. Rec. 1965, 152, 525–535.
  11. Fukuyama, K.; Epstein, W.L. Ultrastructural autoradiographic studies of keratohyalin granule formation. J. Investig. Dermatol. 1967, 49, 595–604.
  12. Fukuyama, K.; Marshburn, I.; Epstein, W.L. Histidine-rich protein in developing rat epidermis. Dev. Biol. 1981, 81, 201–207.
  13. Bernstein, I.A.; Chakrabarti, S.G.; Kumaroo, K.K.; Sibrack, L.A. Synthesis of protein in the mammalian epidermis. J. Investig. Dermatol. 1970, 55, 291–302.
  14. Hoober, J.K. The Differential Incorporation of Amino Acids (In Vivo) into Proteins of the Newborn Rat Epidermis. Ph.D. Thesis, University of Michigan, Ann Arbor, MI, USA, 1965.
  15. Hoober, J.K.; Bernstein, I.A. Studies on the mechanism of the localized incorporation of glycine-H3 in newborn rat epidermis. Fed. Proc. 1963, 22, 238.
  16. Hoober, J.K.; Bernstein, I.A. Protein synthesis related to epidermal differentiation. Proc. Natl. Acad. Sci. USA 1966, 56, 594–601.
  17. Gumucio, J.; Feldkamp, C.; Bernstein, I.A. Studies on localization of “histidine-rich” peptide material present in epidermis of the newborn rat. J. Investig. Dermatol. 1967, 49, 545–551.
  18. Voorhees, J.J.; Siba, M.D.; Chakrabarti, G.; Bernstein, I.A. The metabolism of “histidine-rich” protein in normal and psoriatic keratinization. J. Investig. Dermatol. 1968, 51, 344–354.
  19. Ball, R.D.; Walker, G.K.; Bernstein, I.A. Histidine-rich proteins as molecular markers of epidermal differentiation. J. Biol. Chem. 1978, 253, 5861–5868.
  20. Ugel, A.R. Studies on isolated aggregating oligoribonucleoproteins of the epidermis with histochemical and morphological characteristics of keratohyalin. J. Cell Biol. 1971, 49, 405–422.
  21. Ugel, A.R.; Idler, W. Further characterization of bovine keratohyalin. J. Cell Biol. 1972, 52, 453–464.
  22. Sibrack, L.A.; Gray, R.; Bernstein, I. Localization of the Histidine-Rich Protein in Keratohyalin: A Morphologic and Macromolecular Marker in Epidermal Differentiation. J. Investig. Dermatol. 1974, 62, 394–405.
  23. Balmain, A.; Loehren, D.; Alonso, A.; Goerttler, K. Protein synthesis during fetal development of mouse epidermis. II. Biosynthesis of histidine-rich and cystine-rich proteins in vitro and in vivo. Develop. Biol. 1979, 73, 338–344.
  24. Balmain, A.; Loehren, D.; Fischer, J.; Alonso, A. Protein synthesis during fetal development of mouse epidermis: I. The appearance of “histidine-rich protein”. Dev. Biol. 1977, 60, 442–452.
  25. Brown, S.J.; McLean, W.I. One Remarkable Molecule: Filaggrin. J. Investig. Dermatol. 2012, 132, 751–762.
  26. Dale, B.A. Purification and chaaracterization of a basic protein from the stratum corneum of mammalian epidermis. Biochem. Biophys. Acta 1977, 491, 193–204.
  27. Steinert, P.M.; Cantieri, J.S.; Teller, D.C.; Lonsdale-Eccles, J.D.; Dale, B.A. Characterization of a class of cationic proteins that specifically interact with intermediate filaments. Proc. Natl. Acad. Sci. USA 1981, 78, 4097–4101.
  28. Harding, C.R.; Scott, I.R. Histidine-rich proteins (filaggrins): Structural and functional heterogeneity during epidermal differentiation. J. Mol. Biol. 1983, 170, 651–673.
  29. Steinert, P.M.; Roop, D.R. Molecular and cellular biology of intermediate filaments. Ann. Rev. Biochem. 1988, 57, 593–625.
  30. Fuchs, E.; Green, H. Changes in keratin gene expression during terminal differentiation of the keratinocyte. Cell 1980, 19, 1033–1042.
  31. McKinley-Grant, L.J.; Idler, W.W.; Bernstein, I.A.; Parry, D.A.; Cannizzaro, L.; Croce, C.M.; Huebner, K.; Lessin, S.R.; Steinert, P.M. Characterization of a cDNA clone encoding human filaggrin and localization of the gene to chromosome region 1q21. Proc. Natl. Acad. Sci. USA 1989, 86, 4848–4852.
  32. Resing, K.A.; Johnson, R.S.; Walsh, K.A. Characterization of protease processing sites during conversion of rat proflaggrin to filaggrin. Biochemistry 1993, 32, 10036–10045.
  33. Rothnagel, J.A.; Steinert, P.M. The structure of the gene for mouse filaggrin and a comparison of the repeating units. J. Biol. Chem. 1990, 265, 1862–1865.
  34. Haydock, P.V.; Dale, B.A. Filaggrin, an Intermediate Filament-Associated Protein: Structural and Functional Implications from the Sequence of a cDNA from Rat. DNA Cell Biol. 1990, 9, 251–261.
  35. Presland, R.B.; Haydock, P.V.; Fleckman, P.; Nirunsuksiri, W.; Dale, B.A. Characterization of the human epidermal profilaggrin gene. Genomic organization and identification of an S-100-like calcium binding domain at the amino terminus. J. Biol. Chem. 1992, 267, 23772–23781.
  36. Sandilands, A.; Sutherland, C.; Irvine, A.D.; McLean, W.H.I. Filaggrin in the frontline: Role in skin barrier function and disease. J. Cell Sci. 2009, 122, 1285–1294.
  37. Ishida-Yamamoto, A.; Senshu, T.; Eady, R.A.J.; Takahashi, H.; Shimizu, H.; Akiyama, M.; Iizukz, H. Sequential reorganization of cornified cell keratin filaments involving filaggrin-mediated compaction and keratin 1 dimination. J. Investig. Dermatol. 2002, 118, 282–287.
  38. Presland, R.; Kimball, J.R.; Kautsky, M.B.; Lewis, S.P.; Lo, C.Y.; Dale, B.A. Evidence for Specific Proteolytic Cleavage of the N-Terminal Domain of Human Profilaggrin During Epidermal Differentiation. J. Investig. Dermatol. 1997, 108, 170–178.
  39. Pearton, D.; Nirunsuksiri, W.; Rehemtulla, A.; Lewis, S.P.; Presland, R.; Dale, B.A. Proprotein convertase expression and localization in epidermis: Evidence for multiple roles and substrates. Exp. Dermatol. 2001, 10, 193–203.
  40. Matsui, T.; Miyamoto, K.; Kubo, A.; Kawasaki, H.; Ebihara, T.; Hata, K.; Tanahashi, S.; Ichinose, S.; Imoto, I.; Inazawa, J.; et al. SASPase regulates stratum corneum hydration through profilaggrin-to-filaggrin processing. EMBO Mol. Med. 2011, 3, 320–333.
  41. Leyvraz, C.; Charles, R.-P.; Rubera, I.; Guitard, M.; Rolman, S.; Breiden, B.; Sandhoff, K.; Hummler, E. The epidermal barrier function is dependent upon the serine protease CAP1/Prss8. J. Cell Biol. 2005, 170, 487–496.
  42. List, K.; Szabo, R.; Wertz, P.W.; Segre, J.; Haudenschild, C.C.; Kim, S.-Y.; Bugge, T.H. Loss of proteolytically processed filaggrin caused by epidermal deletion of Matriptase/MT-SP1. J. Cell Biol. 2003, 163, 901–910.
  43. Hsu, C.-Y.; Henry, J.; Raymond, A.-A.; Méchin, M.-C.; Pendaries, V.; Nassar, D.; Simon, M.; Serre, G.; Paul, C.; Takahara, H.; et al. Deimination of human filaggrin-2 promotes its proteolysis by Calpain1. J. Biol. Chem. 2011, 286, 23222–23233.
  44. Hoste, E.; Kemperman, P.; Devos, M.; Denecker, G.; Kezic, S.; Yau, N.; Gilbert, B.; Lippens, S.; De Groote, P.; Roelandt, R.; et al. Caspase-14 Is Required for Filaggrin Degradation to Natural Moisturizing Factors in the Skin. J. Investig. Dermatol. 2011, 131, 2233–2241.
  45. Kamata, Y.; Taniguchi, A.; Yamamoto, M.; Nomura, J.; Ishihara, K.; Takahara, H.; Hibino, T.; Takeda, A. Neutral Cysteine Protease Bleomycin Hydrolase Is Essential for the Breakdown of Deiminated Filaggrin into Amino Acids. J. Biol. Chem. 2009, 284, 12829–12836.
  46. Hanson, K.M.; Simon, J.D. Epidermal trans-urocanic acid and the UV-A-induced photoaging of the skin. Proc. Natl. Acad. Sci. USA 1998, 95, 10576–10578.
  47. Gibbs, N.K.; Norval, M. Urocanic Acid in the Skin: A Mixed Blessing? J. Investig. Dermatol. 2011, 131, 14–17.
  48. Rawlings, A.V.; Harding, C.R. Moisturization and skin barrier function. Dermatol. Ther. 2004, 17, 43–48.
  49. Kezic, S.; Kemperman, P.M.; Koster, E.S.; de Jongh, C.M.; Thio, H.B.; Campbell, L.E.; Irvine, A.; McLean, W.H.I.; Puppels, G.J.; Caspers, P.J. Loss-of-Function Mutations in the Filaggrin Gene Lead to Reduced Level of Natural Moisturizing Factor in the Stratum Corneum. J. Investig. Dermatol. 2008, 128, 2117–2119.
  50. Kezic, S.; Novak, N.; Jakasa, I.; Jungersted, J.M.; Simon, M.; Brandner, J.M.; Middelkamp-Hup, M.A.; Weidinger, S. Skin barrier in atopic dermatitis. Front. Biosci. 2014, 19, 542–556.
  51. De Veer, S.J.; Furio, L.; Harris, J.M.; Hovnanian, A. Proteases: Common culprits in human skin disorders. Trends Mol. Med. 2014, 20, 166–178.
  52. Smith, F.J.D.; Irvine, A.; Terron-Kwiatkowski, A.; Sandilands, A.; Campbell, L.E.; Zhao, Y.; Liao, H.; Evans, A.T.; Goudie, D.R.; Lewis-Jones, S.; et al. Loss-of-function mutations in the gene encoding filaggrin cause ichthyosis vulgaris. Nat. Genet. 2006, 38, 337–342.Smith, F.J.D.; Irvine, A.; Terron-Kwiatkowski, A.; Sandilands, A.; Campbell, L.E.; Zhao, Y.; Liao, H.; Evans, A.T.; Goudie, D.R.; Lewis-Jones, S.; et al. Loss-of-function mutations in the gene encoding filaggrin cause ichthyosis vulgaris. Nat. Genet. 2006, 38, 337–342.
  53. Irvine, A.; McLean, W.H.I.; Leung, D.Y. Filaggrin Mutations Associated with Skin and Allergic Diseases. N. Engl. J. Med. 2011, 365, 1315–1327.Irvine, A.; McLean, W.H.I.; Leung, D.Y. Filaggrin Mutations Associated with Skin and Allergic Diseases. N. Engl. J. Med. 2011, 365, 1315–1327.
  54. McLean, W.H.I. Filaggrin failure—From ichthyosis vulgaris to atopic eczema and beyond. Br. J. Dermatol. 2016, 175 (Suppl. S2), 4–7.McLean, W.H.I. Filaggrin failure—From ichthyosis vulgaris to atopic eczema and beyond. Br. J. Dermatol. 2016, 175 (Suppl. S2), 4–7.
  55. Salama, R.H.; Rasheed, Z.; Ahmed, A.A.; Bin Saif, G.A.; Elkholy, M.M.; El-Moniem, A.E.A.; Salem, T.; Zedan, K.; Al Robaee, A.A.; Alzolibani, A.A. Missense, silent, non-sense and frame-shift mutations in exon 3 of the filaggrin gene in patients with bronchial asthma, atopic dermatitis, allergic rhinitis and mixed atopy. Nucleosides Nucleotides Nucleic Acids 2021, 40, 357–367.Salama, R.H.; Rasheed, Z.; Ahmed, A.A.; Bin Saif, G.A.; Elkholy, M.M.; El-Moniem, A.E.A.; Salem, T.; Zedan, K.; Al Robaee, A.A.; Alzolibani, A.A. Missense, silent, non-sense and frame-shift mutations in exon 3 of the filaggrin gene in patients with bronchial asthma, atopic dermatitis, allergic rhinitis and mixed atopy. Nucleosides Nucleotides Nucleic Acids 2021, 40, 357–367.
  56. Bin, L.; Malley, C.; Taylor, P.; Boorgula, M.P.; Chavan, S.; Daya, M.; Mathias, M.; Shankar, G.; Rafaels, N.; Vergara, C.; et al. Whole genome sequencing identifies novel genetic mutations in patients with eczema herpeticum. Allergy 2021, 76, 2510–2523. Bin, L.; Malley, C.; Taylor, P.; Boorgula, M.P.; Chavan, S.; Daya, M.; Mathias, M.; Shankar, G.; Rafaels, N.; Vergara, C.; et al. Whole genome sequencing identifies novel genetic mutations in patients with eczema herpeticum. Allergy 2021, 76, 2510–2523.
  57. Esparza-Gordillo, J.; Matanovic, A.; Marenholz, I.; Bauerfeind, A.; Rohde, K.; Nemat, K.; Lee-Kirsch, M.-A.; Nordenskjöld, M.; Winge, M.C.G.; Keil, T.; et al. Maternal Filaggrin Mutations Increase the Risk of Atopic Dermatitis in Children: An Effect Independent of Mutation Inheritance. PLoS Genet. 2015, 11, e1005076.Esparza-Gordillo, J.; Matanovic, A.; Marenholz, I.; Bauerfeind, A.; Rohde, K.; Nemat, K.; Lee-Kirsch, M.-A.; Nordenskjöld, M.; Winge, M.C.G.; Keil, T.; et al. Maternal Filaggrin Mutations Increase the Risk of Atopic Dermatitis in Children: An Effect Independent of Mutation Inheritance. PLoS Genet. 2015, 11, e1005076.
  58. Butler, D.C.; Simpson, E.; Guttman-Yassky, E.; Eichenfield, L.F.; Golant, A.K.; Koo, J.Y.M.; Armstrong, A.W.; Alexis, A.F.; Lio, P.A.; Marson, J.W.; et al. The atopic dermatitis spectrum disorder. Recognizing the clinical heterogeneity in patients with atopic related skin conditions in order to improve therapeutic decision-making and outcomes: An expert panel consensus statement. J. Dermatol. Treat. 2021, 33, 1–3.Butler, D.C.; Simpson, E.; Guttman-Yassky, E.; Eichenfield, L.F.; Golant, A.K.; Koo, J.Y.M.; Armstrong, A.W.; Alexis, A.F.; Lio, P.A.; Marson, J.W.; et al. The atopic dermatitis spectrum disorder. Recognizing the clinical heterogeneity in patients with atopic related skin conditions in order to improve therapeutic decision-making and outcomes: An expert panel consensus statement. J. Dermatol. Treat. 2021, 33, 1–3.
  59. Shaw, T.E.; Currie, G.P.; Koudelka, C.W.; Simpson, E.L. Eczema Prevalence in the United States: Data from the 2003 National Survey of Children’s Health. J. Investig. Dermatol. 2011, 131, 67–73.Shaw, T.E.; Currie, G.P.; Koudelka, C.W.; Simpson, E.L. Eczema Prevalence in the United States: Data from the 2003 National Survey of Children’s Health. J. Investig. Dermatol. 2011, 131, 67–73.
  60. Nutten, S. Atopic Dermatitis: Global Epidemiology and Risk Factors. Ann. Nutr. Metab. 2015, 66 (Suppl. S1), 8–16.Nutten, S. Atopic Dermatitis: Global Epidemiology and Risk Factors. Ann. Nutr. Metab. 2015, 66 (Suppl. S1), 8–16.
  61. McAleer, M.A.; Jakasa, I.; Raj, N.; O’Donnell, C.P.F.; Lane, M.E.; Rawlings, A.V.; Irvine, A.D.; Voegeli, R.; McLean, W.H.I.; Kezic, S. Early-life regional and temporal variation in filaggrin-derived moisturizing factor, filaggrin-processing enzyme activity, corneocyte phenotypes and plasmin activity: Implications for atopic dermatitis. Br. J. Dermatol. 2018, 179, 431–441. McAleer, M.A.; Jakasa, I.; Raj, N.; O’Donnell, C.P.F.; Lane, M.E.; Rawlings, A.V.; Irvine, A.D.; Voegeli, R.; McLean, W.H.I.; Kezic, S. Early-life regional and temporal variation in filaggrin-derived moisturizing factor, filaggrin-processing enzyme activity, corneocyte phenotypes and plasmin activity: Implications for atopic dermatitis. Br. J. Dermatol. 2018, 179, 431–441.
  62. Kasparek, P.; Ileninova, Z.; Zbodakova, O.; Kanchev, I.; Benada, O.; Chalupsky, K.; Sedlacek, R.; Brattsand, M.; Beck, I.M. KLK5 and KLK7 ablation fully rescues letahlity of Netherton syndrome-like phenotype. PLoS Genet. 2017, 13, e1006566.Kasparek, P.; Ileninova, Z.; Zbodakova, O.; Kanchev, I.; Benada, O.; Chalupsky, K.; Sedlacek, R.; Brattsand, M.; Beck, I.M. KLK5 and KLK7 ablation fully rescues letahlity of Netherton syndrome-like phenotype. PLoS Genet. 2017, 13, e1006566.
  63. Furio, L.; Pampalakis, G.; Michael, I.; Nagy, A.; Sotiropoulou, G.; Hovnanian, A. KLK5 Inactivation Reverses Cutaneous Hallmarks of Netherton Syndrome. PLoS Genet. 2015, 11, e1005389.Furio, L.; Pampalakis, G.; Michael, I.; Nagy, A.; Sotiropoulou, G.; Hovnanian, A. KLK5 Inactivation Reverses Cutaneous Hallmarks of Netherton Syndrome. PLoS Genet. 2015, 11, e1005389.
  64. Miyai, M.; Matsumoto, Y.; Yamanishi, H.; Yamamoto-Tanaka, M.; Tsuboi, R.; Hibino, T. Keratinocyte-specific mesotrypsin contributes to the desquamation process via kallikrein activation and LEKT1 degradation. J. Investig. Dermatol. 2014, 134, 1665–1674. Miyai, M.; Matsumoto, Y.; Yamanishi, H.; Yamamoto-Tanaka, M.; Tsuboi, R.; Hibino, T. Keratinocyte-specific mesotrypsin contributes to the desquamation process via kallikrein activation and LEKT1 degradation. J. Investig. Dermatol. 2014, 134, 1665–1674.
  65. Briot, A.; Deraison, C.; Lacroix, M.; Bonnart, C.; Robin, A.; Besson, C.; Hovnanian, A.; Dubus, P. Kalikrein 5 induces atopic dermatitis-like lesions through PAR2-mediated thymic stromal lymphopoietin expression in Netherton syndrome. J. Exp. Med. 2009, 206, 1135–1147.Briot, A.; Deraison, C.; Lacroix, M.; Bonnart, C.; Robin, A.; Besson, C.; Hovnanian, A.; Dubus, P. Kalikrein 5 induces atopic dermatitis-like lesions through PAR2-mediated thymic stromal lymphopoietin expression in Netherton syndrome. J. Exp. Med. 2009, 206, 1135–1147.
  66. Kalinin, A.; Marekov, L.N.; Steinert, P.M. Assembly of the epidermal cornified cell envelope. J. Cell Sci. 2001, 114, 3069–3070.Kalinin, A.; Marekov, L.N.; Steinert, P.M. Assembly of the epidermal cornified cell envelope. J. Cell Sci. 2001, 114, 3069–3070.
  67. Candi, E.; Schmidt, R.; Melino, G. The cornified envelope: A model of cell death in the skin. Nat. Rev. Mol. Cell Biol. 2005, 6, 328–340.Candi, E.; Schmidt, R.; Melino, G. The cornified envelope: A model of cell death in the skin. Nat. Rev. Mol. Cell Biol. 2005, 6, 328–340.
  68. Eckert, R.L.; Green, H. Structure and evolution of the human involucrin gene. Cell 1986, 46, 583–589.Eckert, R.L.; Green, H. Structure and evolution of the human involucrin gene. Cell 1986, 46, 583–589.
  69. Eckert, R.L.; Sturniolo, M.T.; Broome, A.-M.; Ruse, M.; Rorke, E.A. Transglutaminase Function in Epidermis. J. Investig. Dermatol. 2005, 124, 481–492.Eckert, R.L.; Sturniolo, M.T.; Broome, A.-M.; Ruse, M.; Rorke, E.A. Transglutaminase Function in Epidermis. J. Investig. Dermatol. 2005, 124, 481–492.
  70. Simon, M.; Green, H. The glutamine residues reactive in transglutaminase-catalyzed cross-linking of involucrin. J. Biol. Chem. 1988, 263, 18093–18098. Simon, M.; Green, H. The glutamine residues reactive in transglutaminase-catalyzed cross-linking of involucrin. J. Biol. Chem. 1988, 263, 18093–18098.
  71. Ishitsuka, Y.; Roop, D.R. Loricrin: Past, present, and future. Int. J. Mol. Sci. 2020, 21, 2271. Ishitsuka, Y.; Roop, D.R. Loricrin: Past, present, and future. Int. J. Mol. Sci. 2020, 21, 2271.
  72. Steinert, P.M.; Marekov, L.N. The Proteins Elafin, Filaggrin, Keratin Intermediate Filaments, Loricrin, and Small Proline-rich Proteins 1 and 2 Are Isodipeptide Cross-linked Components of the Human Epidermal Cornified Cell Envelope. J. Biol. Chem. 1995, 270, 17702–17711.Steinert, P.M.; Marekov, L.N. The Proteins Elafin, Filaggrin, Keratin Intermediate Filaments, Loricrin, and Small Proline-rich Proteins 1 and 2 Are Isodipeptide Cross-linked Components of the Human Epidermal Cornified Cell Envelope. J. Biol. Chem. 1995, 270, 17702–17711.
  73. Matsuki, M.; Yamashita, F.; Ishida-Yamamoto, A.; Yamada, K.; Kinoshita, C.; Fushiki, S.; Yamanishi, K.; Ueda, E.; Tabata, K.; Okabe, M.; et al. Defective stratum corneum and early neonatal death in mice lacking the gene for transaminase 1 (keratinocyte transglutamase). Proc. Natl. Acad. Sci. USA 1998, 95, 1044–1049. Matsuki, M.; Yamashita, F.; Ishida-Yamamoto, A.; Yamada, K.; Kinoshita, C.; Fushiki, S.; Yamanishi, K.; Ueda, E.; Tabata, K.; Okabe, M.; et al. Defective stratum corneum and early neonatal death in mice lacking the gene for transaminase 1 (keratinocyte transglutamase). Proc. Natl. Acad. Sci. USA 1998, 95, 1044–1049.
  74. Liedén, A.; Winge, M.C.G.; Sääf, A.; Kockum, I.; Ekelund, E.; Rodriguez, E.; Fölster-Holst, R.; Franke, A.; Illig, T.; Tengvall-Linder, M.; et al. Genetic Variation in the Epidermal Transglutaminase Genes Is Not Associated with Atopic Dermatitis. PLoS ONE 2012, 7, e49694.Liedén, A.; Winge, M.C.G.; Sääf, A.; Kockum, I.; Ekelund, E.; Rodriguez, E.; Fölster-Holst, R.; Franke, A.; Illig, T.; Tengvall-Linder, M.; et al. Genetic Variation in the Epidermal Transglutaminase Genes Is Not Associated with Atopic Dermatitis. PLoS ONE 2012, 7, e49694.
  75. Su, H.; Luo, Y.; Sun, J.; Liu, X.; Ling, S.; Xu, B.; Zhang, Y.; Liu, J.; Li, W.; Wang, B.; et al. Transglutaminase 3 Promotes Skin Inflammation in Atopic Dermatitis by Activating Monocyte-Derived Dendritic Cells via DC-SIGN. J. Investig. Dermatol. 2020, 140, 370–379.Su, H.; Luo, Y.; Sun, J.; Liu, X.; Ling, S.; Xu, B.; Zhang, Y.; Liu, J.; Li, W.; Wang, B.; et al. Transglutaminase 3 Promotes Skin Inflammation in Atopic Dermatitis by Activating Monocyte-Derived Dendritic Cells via DC-SIGN. J. Investig. Dermatol. 2020, 140, 370–379.
  76. Griffin, M.; Casadio, R.; Bergamini, C.M. Transglutaminases: Nature’s biological glues. Biochem. J. 2002, 368, 377–396.Griffin, M.; Casadio, R.; Bergamini, C.M. Transglutaminases: Nature’s biological glues. Biochem. J. 2002, 368, 377–396.
  77. Chou, C.-Y.; Streets, A.J.; Watson, P.F.; Huang, L.; Verderio, E.A.; Johnson, T.S. A Crucial Sequence for Transglutaminase Type 2 Extracellular Trafficking in Renal Tubular Epithelial Cells Lies in Its N-terminal β-Sandwich Domain. J. Biol. Chem. 2011, 286, 27825–27835. Chou, C.-Y.; Streets, A.J.; Watson, P.F.; Huang, L.; Verderio, E.A.; Johnson, T.S. A Crucial Sequence for Transglutaminase Type 2 Extracellular Trafficking in Renal Tubular Epithelial Cells Lies in Its N-terminal β-Sandwich Domain. J. Biol. Chem. 2011, 286, 27825–27835.
  78. Zemskov, E.A.; Mikhailenko, I.; Hsia, R.-C.; Zaritskaya, L.; Belkin, A.M. Unconventional Secretion of Tissue Transglutaminase Involves Phospholipid-Dependent Delivery into Recycling Endosomes. PLoS ONE 2011, 6, e19414. Zemskov, E.A.; Mikhailenko, I.; Hsia, R.-C.; Zaritskaya, L.; Belkin, A.M. Unconventional Secretion of Tissue Transglutaminase Involves Phospholipid-Dependent Delivery into Recycling Endosomes. PLoS ONE 2011, 6, e19414.
  79. Nurminskaya, M.V.; Belkin, A.M. Cellular Functions of Tissue Transglutaminase. Int. Rev. Cell. Mol. Biol. 2012, 294, 1–97.Nurminskaya, M.V.; Belkin, A.M. Cellular Functions of Tissue Transglutaminase. Int. Rev. Cell. Mol. Biol. 2012, 294, 1–97.
  80. Telei, D.; Griffin, M. Tissue transaminase (TG2)—A wound response enzyme. Front. Biosci. 2006, 11, 867–882.Telei, D.; Griffin, M. Tissue transaminase (TG2)—A wound response enzyme. Front. Biosci. 2006, 11, 867–882.
  81. Stephens, P.; Grenard, P.; Aeschlimann, P.; Langley, M.; Blain, E.; Errington, R.; Kipling, D.; Thomas, D.; Aeschlimann, D. Crosslinking and G-protein functions of transglutaminase 2 contribute differentially to fibroblast wound healing responses. J. Cell Sci. 2004, 117, 3389–3403.Stephens, P.; Grenard, P.; Aeschlimann, P.; Langley, M.; Blain, E.; Errington, R.; Kipling, D.; Thomas, D.; Aeschlimann, D. Crosslinking and G-protein functions of transglutaminase 2 contribute differentially to fibroblast wound healing responses. J. Cell Sci. 2004, 117, 3389–3403.
  82. Haroon, Z.A.; Hettasch, J.M.; Lai, T.-S.; Dewhirst, M.W.; Greenberg, C.S. Tissue transglutaminase is expressed, active, and directly involved in rat dermal wound healing and angiogenesis. FASEB J. 1999, 13, 1787–1795. Haroon, Z.A.; Hettasch, J.M.; Lai, T.-S.; Dewhirst, M.W.; Greenberg, C.S. Tissue transglutaminase is expressed, active, and directly involved in rat dermal wound healing and angiogenesis. FASEB J. 1999, 13, 1787–1795.
  83. Verderio, E.A.M.; Johnson, T.; Griffin, M. Tissue transglutaminase in normal and abnormal wound healing: Review article. Amino Acids 2004, 26, 387–404.Verderio, E.A.M.; Johnson, T.; Griffin, M. Tissue transglutaminase in normal and abnormal wound healing: Review article. Amino Acids 2004, 26, 387–404.
  84. Johnson, T.S.; Scholfield, C.I.; Parry, J.; Griffin, M. Induction of tissue transglutaminase by dexamethasone: Its correlation to receptor number and transglutaminase-mediated cell death in a series of malignant hamster fibrosarcomas. Biochem. J. 1998, 331, 105–112.Johnson, T.S.; Scholfield, C.I.; Parry, J.; Griffin, M. Induction of tissue transglutaminase by dexamethasone: Its correlation to receptor number and transglutaminase-mediated cell death in a series of malignant hamster fibrosarcomas. Biochem. J. 1998, 331, 105–112.
  85. Pinkas, D.; Strop, P.; Brunger, A.; Khosla, C. Transglutaminase 2 Undergoes a Large Conformational Change upon Activation. PLoS ONE 2007, 5, e327. Pinkas, D.; Strop, P.; Brunger, A.; Khosla, C. Transglutaminase 2 Undergoes a Large Conformational Change upon Activation. PLoS ONE 2007, 5, e327.
  86. Mearns, B.; Nanda, N.; Michalieck, J.; Iismaa, S.; Graham, R. Impaired wound healing and altered fibroblast cytoskeletal dynamics in Gh knockout mice. Minerva Biotecnol. 2002, 14, 218.Mearns, B.; Nanda, N.; Michalieck, J.; Iismaa, S.; Graham, R. Impaired wound healing and altered fibroblast cytoskeletal dynamics in Gh knockout mice. Minerva Biotecnol. 2002, 14, 218.
  87. Elias, P.M. Epidermal lipids, barrier function, and desquamation. J. Investig. Dermatol. 1983, 80, 544–549.Elias, P.M. Epidermal lipids, barrier function, and desquamation. J. Investig. Dermatol. 1983, 80, 544–549.
  88. Nemes, Z.; Steinert, P.M. Bricks and mortar of the epidermal barrier. Exp. Mol. Med. 1999, 31, 5–19.Nemes, Z.; Steinert, P.M. Bricks and mortar of the epidermal barrier. Exp. Mol. Med. 1999, 31, 5–19.
  89. Grubauer, G.; Elias, P.M.; Feingold, K.R. Transepidermal water loss: The signal for recovery of barrier structure and function. J. Lipid Res. 1989, 30, 323–333.Grubauer, G.; Elias, P.M.; Feingold, K.R. Transepidermal water loss: The signal for recovery of barrier structure and function. J. Lipid Res. 1989, 30, 323–333.
  90. Elias, P.M.; Wakefield, J.S. Mechanisms of abnormal lamellar body secretion and the dysfunctional skin barrier in patients with atopic dermatitis. J. Allergy Clin. Immunol. 2014, 134, 781–791.e1.Elias, P.M.; Wakefield, J.S. Mechanisms of abnormal lamellar body secretion and the dysfunctional skin barrier in patients with atopic dermatitis. J. Allergy Clin. Immunol. 2014, 134, 781–791.e1.
  91. Caubet, C.; Jonca, N.; Brattsand, M.; Guerrin, M.; Bernard, D.; Schmidt, R.; Egelrud, T.; Simon, M.; Serre, G. Degradation of Corneodesmosome Proteins by Two Serine Proteases of the Kallikrein Family, SCTE/KLK5/hK5 and SCCE/KLK7/hK7. J. Investig. Dermatol. 2004, 122, 1235–1244.Caubet, C.; Jonca, N.; Brattsand, M.; Guerrin, M.; Bernard, D.; Schmidt, R.; Egelrud, T.; Simon, M.; Serre, G. Degradation of Corneodesmosome Proteins by Two Serine Proteases of the Kallikrein Family, SCTE/KLK5/hK5 and SCCE/KLK7/hK7. J. Investig. Dermatol. 2004, 122, 1235–1244.
  92. Igawa, S.; Kishibe, M.; Honma, M.; Murakami, M.; Mizuno, Y.; Suga, Y.; Seishima, M.; Ohguchi, Y.; Akiyama, M.; Hirose, K.; et al. Aberrant distribution patterns of corneodesmosomal components of tape-stripped corneocytes in atopic dermatitis and related skin conditions (ichthyosis vulgaris, Netherton syndrome and peeling skin syndrome type B). J. Dermatol. Sci. 2013, 72, 54–60. Igawa, S.; Kishibe, M.; Honma, M.; Murakami, M.; Mizuno, Y.; Suga, Y.; Seishima, M.; Ohguchi, Y.; Akiyama, M.; Hirose, K.; et al. Aberrant distribution patterns of corneodesmosomal components of tape-stripped corneocytes in atopic dermatitis and related skin conditions (ichthyosis vulgaris, Netherton syndrome and peeling skin syndrome type B). J. Dermatol. Sci. 2013, 72, 54–60.
  93. Simon, M.; Montézin, M.; Guerrin, M.; Durieux, J.-J.; Serre, G. Characterization and Purification of Human Corneodesmosin, an Epidermal Basic Glycoprotein Associated with Corneocyte-specific Modified Desmosomes. J. Biol. Chem. 1997, 272, 31770–31776.Simon, M.; Montézin, M.; Guerrin, M.; Durieux, J.-J.; Serre, G. Characterization and Purification of Human Corneodesmosin, an Epidermal Basic Glycoprotein Associated with Corneocyte-specific Modified Desmosomes. J. Biol. Chem. 1997, 272, 31770–31776.
  94. Guerrin, M.; Simon, M.; Montézin, M.; Haftek, M.; Vincent, C.; Serre, G. Expression Cloning of Human Corneodesmosin Proves Its Identity with the Product of the S Gene and Allows Improved Characterization of Its Processing during Keratinocyte Differentiation. J. Biol. Chem. 1998, 273, 22640–22647.Guerrin, M.; Simon, M.; Montézin, M.; Haftek, M.; Vincent, C.; Serre, G. Expression Cloning of Human Corneodesmosin Proves Its Identity with the Product of the S Gene and Allows Improved Characterization of Its Processing during Keratinocyte Differentiation. J. Biol. Chem. 1998, 273, 22640–22647.
  95. Riethmuller, C.; McAleer, M.A.; Koppes, S.A.; Abdayem, R.; Franz, J.; Haftek, M.; Campbell, L.E.; MacCallum, S.F.; McLean, W.I.; Irvine, A.D.; et al. Filaggrin breakdown products determine corneocyte conformation in patients with atopic dermatitis. J. Allergy Clin. Immunol. 2015, 136, 1573–1580.e2.Riethmuller, C.; McAleer, M.A.; Koppes, S.A.; Abdayem, R.; Franz, J.; Haftek, M.; Campbell, L.E.; MacCallum, S.F.; McLean, W.I.; Irvine, A.D.; et al. Filaggrin breakdown products determine corneocyte conformation in patients with atopic dermatitis. J. Allergy Clin. Immunol. 2015, 136, 1573–1580.e2.
More
© Text is available under the terms and conditions of the Creative Commons Attribution (CC BY) license (http://creativecommons.org/licenses/by/4.0/)
Video Production Service
Feedback