Proline Isomerization in Human Disease: History
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Please note this is an old version of this entry, which may differ significantly from the current revision.
Contributor:
Deepti Gurung
,
Jacob A Danielson
,
Afsara Tasnim
,
Jian-Ting Zhang
,
Yue Zou
,
Jing-Yuan Liu

Proline isomerization influences protein folding and function tremendously and serves as a unique type of post-translational modification that regulates multiple biological pathways. Although impactful, the importance and prevalence of proline isomerization as a regulation mechanism in biological systems has not been fully understood or recognized. 

  • proline isomerization
  • post-translation modifications
  • proline isomerase
  • cyclophilin
  • cyclosporin
  • FK506 binding protein (FKBP)

  1. Introduction

Isomers are a group of molecules that have the same composition of atoms but differ in the 3-dimensional arrangement of these atoms. Isomerization is a process in which one isomer undergoes structural changes to produce a different isomer. Isomerization can occur through bond rotations or rearrangement reactions. Cis/trans isomerization, also known as geometric isomerization, is a type of isomerization in which a molecule changes its spatial arrangement around a double bond or a ring structure. In a cis-isomer, the functional groups of interest are on the same side of a double bond or a ring, while in a trans-isomer, they are on opposite sides. Cis/trans isomerization switches a cis-isomer into a trans-isomer and vice versa.

2. Autoimmune Disease

The recognition of the link between proline isomerization and immunity has a long-standing history as evidenced by the fact that the first PPIase, Cyclophilin A, was discovered during the search for the protein target of the immunosuppressive drug cyclosporin. It is therefore no surprise that research groups discovered that proline isomerization plays critical roles in modulating immune cell activation and immune tolerance, concluding that dysregulation of PPIase activity may contribute to autoimmunity.
Multiple sclerosis (MS) is a chronic and progressive autoimmune disorder characterized by the immune system targeting the myelin sheath in the central nervous system. The hallmark features of MS include axonal injury, neuronal loss, and central nervous system atrophy [1][2], which are thought to result from the accumulation of reactive oxygen species, neuronal Ca2+ overload, and the activation of Ca2+-dependent cysteine proteases called calpains [3][4]. CypD is a key regulator of the mitochondrial permeability transition pore (mPTP), which is a non-specific channel in mitochondrial inner membrane that facilitates the entry of small molecules (<1.5 kDa) into mitochondria. The binding of CypD to mPTP leads to the formation of a channel that allows the influx of solutes up to 1.5 kDa, which can trigger mitochondrial swelling and rupture, and subsequent cytochrome C release and cell death. In studies using an animal model for MS, CypD knockout mice showed better recovery from MS compared to control mice [5]. Additionally, selective inhibition of CypD in neuronal cells by a CypD inhibitor, JW47, showed significant protection of axons in the experimental model. This neuroprotective effect of JW47 was due to its direct inhibition of Ca2+-mediated mPTP formation [6]. Therefore, inhibition of CypD–mPTP interaction can protect against axonal injury and neurodegeneration, highlighting the potential of this pathway as a target for MS treatment.
Recent research by Ge et al. in 2021 has shown that inhibition of Pin1 by juglone, a Pin1 inhibitor, can also significantly reduce inflammation and demyelination in a mouse model of MS called experimental autoimmune encephalomyelitis [7]. This effect was achieved through the suppression of CD4+ T-cells that produce IFN-β and IL-2, specifically Th1 and Th17 cells. It is well-established that CD4+ T-cells primed against myelin oligodendrocyte glycoprotein antigen are involved in MS pathogenesis [8]. Furthermore, Juglone treatment also resulted in the suppression of the costimulatory molecule CD38 in dendritic cells, suggesting a pathogenic role for Pin1 in MS [7]. In addition, myelin basic protein (MBP), a critical component of the myelin sheath in the central nervous system, contains proline-rich motifs and has been identified as a ligand for Fyn-SH3 (Src homology 3) domain [9]. This has led to the speculation that proline isomerization, specifically through Pin1, could potentially modulate MBP function and contribute to MS [10][11][12]. Evidently, future studies to elucidate the detailed mechanism and to explore Pin1 inhibition as a potential therapeutic strategy are essential to develop novel methods for MS treatment.
Systemic lupus erythematosus (SLE) is a systemic autoimmune disease that can affect multiple organs such as skin, lungs, heart, kidneys, muscles, and joints. One of the prominent molecular hallmarks in SLE patients is increased Type 1 IFN in their serum, which is produced primarily by myeloid cells [12][13]. The elevated production of Type 1 IFN leads to hypergammaglobulinemia in the following steps: (i) breakdown of immune tolerance, which normally prevents the immune system from attacking self-tissues, (ii) activation of autoreactive B cells, leading to the production of autoantibodies against self-antigens, (iii) autoantibodies then form immune complexes, which deposit in various tissues and organs, causing inflammation and tissue damage. In addition, type 1 IFN can also enhance the survival and activation of B cells, which are responsible for producing autoantibodies [12][14][15][16]. Tun-Kyi et al. reported the role of Pin1 in Toll-like receptor (TLR) signaling and type 1 IFN activation using bone marrow-derived myeloid dendritic cells from mice in 2011 [17]. Pin1 is activated by the activation of TLR7 and TLR9 in response to foreign DNA signatures. Pin1 then binds to IL-1 receptor-associated kinase-1 (IRAK1), inducing conformational changes that promote dissociation from the Myddosome receptor complex and its activation. This facilitates the activation of the transcription factor Interferon Regulatory Factor 7 (IRF7) and induces the production of type 1 IFN. Wei et al. connected the link between Pin1-mediated production of type 1 IFN via TLR-7/TLR-9/IRAK-1/IRF-7 signaling and the development of SLE in 2016 [18]. They observed that Pin1 activity is elevated in monocytes from SLE patients compared to control groups. Furthermore, in vitro Pin1 knockdown, or treatment of cells with Pin1 inhibitor All-trans retinoic acid (ATRA), suppresses Pin1/IRAK-1/IRK-7. In addition, ATRA treatment of a lupus-prone mice model significantly reduced SLE-related phenotypes. Therefore, targeting Pin1-mediated production of type 1 IFN via TLR-7/TLR-9/IRAK-1/IRF-7 signaling may provide a promising novel therapeutic approach for SLE treatment and further studies are clearly warranted.
In addition, recent research has identified Pin1 as an important regulator of IL-6 expression in SLE [19]. IL-6 is a pro-inflammatory cytokine that plays a key role in the differentiation of B cells into antibody-producing plasma cells, differentiation of CD4 naïve T-cells into Th17 cells, and differentiation of CD8+ T-cells into cytotoxic T-cells [20]. Dysregulation of IL-6 production can result in autoantibody production, contributing to SLE by promoting the survival and differentiation of autoreactive B cells, which produce antibodies that target self-tissues. IL-6 expression blockade greatly improved the phenotype in SLE [21]. IL-6 signaling is mediated by the IL-6 receptor (IL-6R) and the signal transducer and activator of transcription 3 (STAT3), and dysregulation of this pathway has been implicated in the pathogenesis of several diseases, including cancer and autoimmune disorders. Pin1 interacts with STAT3, promoting its phosphorylation and nuclear localization [22]. Pin1 inhibition in Juglone-treated NZB/W F1 lupus mice resulted in suppression of B-cell differentiation and T-cell activation compared to non-treated mice. Furthermore, decreased STAT3 phosphorylation was observed in T-cells of Juglone-treated mice [19]. These findings suggest that Pin1 plays a critical role in regulating IL-6 signaling and may contribute to the pathogenesis of SLE.
As well as multiple sclerosis and systemic lupus erythematosus, CypA has been found to be associated with rheumatoid arthritis (RA), which is characterized by chronic inflammation of joints that leads to severe pain, swelling, and stiffness of joints. The chronic inflammation can gradually erode the cartilage and bone within the joints, causing deformity, and eventually loss of function of the affected joints. The secreted form of CypA is found to be elevated in the synovial fluids of rheumatoid arthritis patients and macrophages in the synovial lining layer are the major source of this CypA [23][24]. CypA contributes to the destruction of cartilage and bone by upregulating MMP-9 (Matrix Metalloproteinase-9) expression and adhesion of monocytes/macrophages to extracellular matrix [25]. CypA also affects IL-8-directed chemotaxis in neutrophils of RA patients and is responsible for CypA-mediated neutrophil migration into the joints, elevated MMPs secretion, and cell invasion of synoviocytes, which are key pathological mechanisms of RA [26][27][28][29].

3. Cancer

Cancer is a highly intricate and constantly evolving disease that arises as a result of often multifactorial interactions between genomic, epigenomic, proteomic, and environmental factors. It represents a complex and heterogeneous class of disorders characterized by a diverse array of molecular and cellular aberrations, including dysregulated proliferation, impaired cell death, genomic instability, and immune evasion. Since proline isomerization mediated by prolyl isomerases is a critical post-translational modification that regulates protein folding, stability, and function, emerging evidence suggests that aberrant expression of prolyl isomerases can contribute to the pathogenesis of cancer by affecting a wide range of oncogenic signaling pathways, including DNA repair, cell cycle regulation, apoptosis, and immune surveillance. A large-scale human tissue microarray study compared normal and cancerous tissues to reveal that the protein expression level of Pin1 is significantly overexpressed in most common cancers including prostate, breast, lung, and colon cancer [30]. Studies revealed overexpression of Pin1 in both mRNA and protein levels for oral squamous cell carcinoma [31][32], gastric cancer [33], and acute myeloid leukemia [34], and only at the protein level in colorectal cancer [35][36], osteosarcoma [37], and pancreatic cancer [38]. Recently in 2023, Naito et al. reported that Par14 is overexpressed in prostate cancer, and it promotes proliferation by directly binding to the androgen receptor and regulating androgen receptor signaling pathways [39]. On the other hand, FKBPs (mainly FKBP51 and FKBP52) and Cyp40 are overexpressed in steroid hormone-dependent cancers such as breast and prostate cancer [40][41][42]. Recently, a few groups have reported overexpression of FKBP10, FKBP11, FKBP5 in renal cancer and hepatocellular carcinoma [43][44][45].
Overexpression of Pin1 has been correlated with the poor clinical outcome of cancer patients by affecting multiple oncogenic signaling pathways [46][47][48]. Pin1 was first described as a mitotic regulator of cyclin D1 in HeLa cells [49]; overexpression of Pin1 increases the cyclin D1 level by multiple signaling pathways including C-Jun/Fos, β-catenin, and NF-Kβ [49][50][51]. Moreover, Pin1 directly binds and activates 56 oncogenic proteins and inactivates 26 tumor suppressors [52]. The cis/trans isomerization also stabilizes and increases the half-life of oncogenic proteins by preventing their nuclear localization and degradation via the ubiquitination–proteasome pathway [53]. Pin1 knockout and/or knockdown induces apoptosis, and suppression of oncogenesis both in vitro and in vivo [54][55][56][57][58]. The rs2233678 polymorphism in the Pin1 promoter region (-842 G > C) has been shown to decrease the risk of cancers including breast cancer [59][60]. There are 32 somatic mutations reported in the Pin1 gene among different types of cancer suggesting a correlation between Pin1 mutation and the increased risk of cancer [61]. Additionally, Pin1 also plays a role in centrosome amplification and genomic stability [62]. Pin1 mediates tamoxifen resistance in the MCF-7 breast cancer cell line by increasing the mRNA and protein expression of LC-3, a marker for autophagy, which is believed to be utilized by cancer cells as a coping scheme for survival at the point of drug selection [63]. Pin1-dependent vascular endothelial growth factor (VEGF) production in MCF-7 cells was observed in tamoxifen resistant cells [64]. Wang et al. showed that Pin1 mediated cisplatin resistance in cervical cancer via the FOXM1/WNT-β-catenin signaling pathway in 2016 [65]. In addition, some studies revealed new insights regarding Pin1 as a potential regulator for induction and maintenance of pluripotent stem cells via the regulation of Oct4, which is an imperative transcription factor for embryonic stem cells [66]. Despite most studies suggesting Pin1 is pro-cancerous, it has also been observed that Pin1’s high expression correlates with a better prognosis in melanoma, prostate, and testis cancer patients, as revealed from a bioinformatics analysis of tumors in the Human Protein Atlas [67]. They suggested that the relationship between p53 and Pin1 expression in cancer cells may explain this phenotype. Pin1-mediated isomerization of wild-type p53 can potentially activate its tumor-suppressive functions, whereas mutant p53, which is more prevalent in cancer, may activate its oncogenic function. Taken together, the above findings suggest that Pin1’s function in cancer cells can be complicated and whether Pin1 is pro or against cancer cell growth depends on the tissue and the existence and status of other protein factors. Therefore, future research delineating Pin1’s function in different cell types and genetic background is greatly needed and would be important to determine Pin1 as a target for cancer therapy, which is also highly relevant to precision medicine.
FKBPs, such as FKBP5, FKBP51, and FKBP52, are important components of steroid hormone receptor-Hsp90 complex [40][68]. They directly bind to Hsp90, via their TPR domains, and serve as co-chaperones [69]. FKBP52 binds to androgen receptor (AR) [70], estrogen receptor α (ERα) [42], glucocorticoid receptor (GR) [71], and progesterone receptor (PR) [72] in the nucleus. Maeda et al. reported that FKBP52 regulates dimerization of AR in 2022 [73]. Similar to Pin1, these interactions lead to increased transcriptional activity of these receptors, which leads to cell proliferation in breast and prostate cancer. FKBP51 also mediates radio-resistance in malignant melanomas via regulation of the NF-Kβ pathway [74].
Cyp40 can also bind to the Hsp90-ERα complex and increase the transcriptional activity of the receptor [75]. Additionally, Cyp40 siRNA experiments in ALK+ ALCL cell lines directed the potential role of Cyp40 in oncogenesis in lymphoma. The role of PPIases in cancer has been reviewed by several other authors and it is recommended to refer to them for more in-depth information [69][76][77][78].

4. Infectious Disease

Prolyl isomerases have been known to play a significant role in various stages of viral propagation. HIV-1 (Human Immunodeficiency Virus type 1) provided the most prominent example of proline isomerization in viral pathogenesis for the first time. Two distinct PPIases, human CypA and Pin1, have been found to play an important role in the life cycle of HIV and induce viral pathological effects in humans. The mature HIV-1 capsid is a fullerene cone-shaped structure composed of 125 hexametric and 12 pentameric units. Hexametric units consist of 6 p24 molecules arranged in a circular ring, stacked on top of each other to form a lattice structure that makes up the bulk of the capsid, while pentameric units consist of 5 p24 molecules arranged in a pentagonal ring, and they are located at the narrow end of the cone and stabilize the overall structure [79]. The capsid core is responsible for aiding viral infection by interacting with host cells, transporting the viral genome and the reverse transcriptase machinery to the host nucleus [80]. Since the first evidence of interaction between CypA and HIV-1 was found [81], several independent groups have shown that the incorporation of CypA into HIV particles facilitates HIV replication, maturation, and infectivity [82][83][84]. The underlying mechanism has been deciphered by the collective works using both crystallography and NMR spectroscopy [81][85][86]. When the virus is transported to the host cell, CypA binds to the capsid and catalyzes proline isomerization at the Gly89-Pro90 site in the capsid protein, leading to conformational changes that increase the affinity between CypA and capsid and the formation of a stable complex that is important for unpacking the capsid. The N-terminal domain of the HIV-1 capsid (residues 1-151) has been captured complexed with CypA by X-ray crystallography [85] (PDB: 1AK4). Specifically, the active site of CypA was found to bind to a flexible and exposed loop region (residues 85-93) of the capsid protein located between helix 4 and 5 on the N-terminal domain. Additionally, it was found that the CypA-capsid interaction also prevents the binding of and replication restriction from human TRIM5α. Genetic tools and functional assays have shown that disrupting the CypA–capsid interaction can render HIV-1 susceptible to endogenous TRIM5α [87].
In addition to CypA, Pin1 also plays a significant role in facilitating the life cycle of HIV-1 and promoting infection. Pin1 is involved in several key processes including capsid core uncoating, reverse transcription, and integration. In 2010, Misumi et al. reported that Pin1 interacts with the HIV capsid and the proline isomerization is essential for capsid–capsid protein dissociation and disassembly of the HIV-1 core into the host cells at the early stage of the HIV-1 life cycle [88]. Using Pin1 pull-down assay, they showed that Pin1 binds preferentially at the pSer16-Pro17 motif in HIV-1 capsid proteins. The results indicate that the capsid core, which has been phosphorylated within the viral particle following its release from infected cells, binds directly to Pin1 upon entering host cells and then undergoes an uncoating process. Furthermore, restrictions in reverse transcription and HIV-1 replication were observed when a double mutation S16A/P17A was introduced to the capsid. Additionally, suppressing Pin1 expression led to the attenuation of HIV-1 replication and resulted in the accumulation of capsid core particulates in the cytosol of the host cells.
In addition to its role in promoting HIV uncoating and replication, Pin1 also binds and inhibits APOBEC3G, a cytidine deaminase protein that has antiviral activity, by restricting HIV-1 replication, leading to its degradation via proteasome [89]. This degradation mechanism was originally thought to be mediated solely by HIV-1’s viral infectivity factor (Vif), a viral protein [90]. Therefore, Pin1-mediated depletion of APOBEC3G represents a novel mechanism of its degradation. Pin1 has been shown to promote viral genome integration into the host cell genome. This is mediated by the JNK-mediated phosphorylation of the Ser57-Pro58 motif of HIV-integrase via the NF-Kβ signaling pathway [91][92].
In comparison to cyclophilins and Pin1, the role of FKBPs in HIV infection is not as clear. However, recently, CRISPR-Cas9 screening and co-immunoprecipitation assay showed that FKBP3 indirectly binds with HIV-1-long terminal repeats (HIV-LTR) and through YY1 and HDAC 1/2 proteins [93]. These interactions allow histone deacetylation of HIV-LTR which is shown to be associated with inhibition of HIV replication and promotion of HIV-1 latency.
Apart from HIV, hepatitis C virus (HCV) is the most widely studied viral model system to understand the mechanism of viral replication. The insight into the role of cyclophilins in HCV replication came from in vitro cyclosporin inhibition of HCV replication [94][95]. It was demonstrated that CypA and CypB bind with HCV NS5A/B, an RNA-dependent RNA polymerase, promoting its RNA-binding activity and thereby HCV replication [96][97]. Although the crystal structure of CypA/B with NSB5A/B has not yet been solved, Li et al. predicted their complex structure using protein–protein docking and molecular dynamics simulation and suggested in 2022 that the hydrophobic pocket (Ile57, Phe60, Trp105, Trp121) of CypA interacts with the proline-rich D2 domain of NS5A [98]. The exact mechanism underlying the isomerization and hard evidence depicting the complex structure of CypA-NS5A has yet to be elucidated. Interestingly, Pin1 has also been shown to bind directly to both NS5A and NS5B and to modulate HCV replication [99]. In addition to cyclophilins and Pin1, FKBP, especially FKBP8, has also been shown to bind with NS5A of HCV via its TPR domain by immunoprecipitation assay, which promotes HCV replication [100] .
As well as HIV and HCV, there is evidence to show PPIases also impact on hepatitis B virus (HBV) replication and virion secretion. Pin1 stabilizes the hepatitis B virus by directly binding to two separate proteins, HBV core protein and HBV X protein. These proteins are vital for maintaining HBV genome integrity and replication. Dephosphorylation at the sites Thr160 and Ser162 of HBV core protein results in the loss of Pin1 binding and degradation of HBV core protein by lysosome [101]. Pin1 can also bind to the highly conserved Ser41-Pro42 sequence of HBV X and stabilize the protein, which contributes to viral replication and viral entry into the host cells [102][103]. Interestingly, this interaction has also been indicated to play a role in virus-induced tumorigenesis, i.e., hepatocarcinogenesis [101]. Furthermore, Par14 and Par17 can also promote HBV virus replication through formation of a ternary complex with covalently closed circular DNA and HBX protein [104]. As well as Pin1, there is limited information on FKBPs in relation to HBV, but there is some indirect evidence suggesting the involvement of cyclophilins. Using cyclophilin inhibitors and RNA interference experiments, several groups have shown that CypA directly binds to HBX [105], and promotes HBV replication, production and secretion [106][107][108]. Finally, to conclude this section, the connection between PPIases and viral infections covered here is far from being complete and one can refer to additional review articles by Yamamoto et al. [109], Wu et al. [110] and Kanna et al. [111] to access more comprehensive details regarding other viral infections, including SARS-CoV.

5. Neurodegenerative Disease

Neurodegenerative diseases, such as Alzheimer’s disease (AD) and Parkinson’s disease (PD), are primarily characterized by the progressive loss of neurons. Prolyl isomerases are expressed at higher levels in neurons than in other differentiated cells. Numerous studies have demonstrated the protective role of proline isomerization during neuronal differentiation. Consequently, prolyl isomerase dysregulation has been associated with abnormal aggregation of neuronal substrates, including tau, amyloid precursor proteins (APP), and α-synuclein in age-dependent neurodegenerative diseases.
In Alzheimer’s disease, the accumulation of proteins such as tau and APP into plaques is believed to be partly caused by changes in proline isomerization. The cis/trans isomerization of the pThr231-Pro232 motif in tau mediated by Pin1 plays a crucial role in the development and progression of AD and tauopathies [112]. Trans-tau promotes the health of neurons, while the cis-isomer of tau has been linked to AD-like symptoms, including decreased microtubule formation, increased tau phosphorylation, aggregation, and tangle formation which led to neuronal apoptosis, and neurodegeneration [113]. Pin1 regulates tau by converting cis-tau to trans-tau, which then binds to microtubules and maintains their dynamics. Additionally, Pin1-deficient mice have been found to display tau pathology and neuronal loss. In addition to tau, Pin1-mediated isomerization of the APP protein has also been linked to AD. Pin1 binds and catalyzes the pThr668-Pro669 motif in APP [114]. Isomerization from cis- to trans-APP results in the stabilization of APP in plasma membrane and decreased protein turnover of APP, which leads to a decrease in the activity of Glycogen Synthase Kinase 3 Beta (GSK3β), a detrimental factor in neuronal death, and inhibition of APP binding to Fe65, which modulates trafficking and proteolytic processing and production of β-amyloid peptides that lead to neuronal apoptosis when binding to the intracellular domain of APP [115]. In contrast, the cis-isomer of APP promotes an increase in β-amyloid peptide production, resulting in plaque formation and the amyloidogenic processing pathway [116]. This effect is also observed when Pin1 levels are low in neurons. Altogether, this evidence indicates the protective role of Pin1 in AD.
Parkinson’s disease (PD) has been linked to the pathogenesis of α-synuclein, as indicated by the presence of amyloid-like aggregates of α-synuclein in the brains of PD patients. In addition to its role in AD, Pin1 has also been found to accumulate and co-localize with α-synuclein inclusions in the Lewy bodies of human PD brains [117]. Pin1 promotes the formation of α-synuclein inclusions by stabilizing α-synuclein and enhancing its binding with synphilin-1. In addition to Pin1, it has been shown that CypA binds and catalyzes the proline isomerization of Pro128 located at the C-terminus of α-synuclein, resulting in misfolding and aggregation [118]. Moreover, FKBP12 has also been associated with α-synuclein aggregation [119]. More detailed information on the role of Pin1 in neuronal signaling can be found in the review by Fagiani et al. in 2021 [120].
 
 
 

This entry is adapted from the peer-reviewed paper 10.3390/biology12071008

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