Autophagy in Crohn’s Disease: History
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Contributor:
Kibrom M. Alula
,
Arianne L. Theiss

Crohn’s disease (CD) is a chronic inflammatory bowel disease marked by relapsing, transmural intestinal inflammation driven by innate and adaptive immune responses. Autophagy is a multi-step process that plays a critical role in maintaining cellular homeostasis by degrading intracellular components, such as damaged organelles and invading bacteria. Dysregulation of autophagy in CD is revealed by the identification of several susceptibility genes, including ATG16L1, IRGM, NOD2, LRRK2, ULK1, ATG4, and TCF4, that are involved in autophagy.

  • Crohn’s disease
  • innate immunity
  • mitophagy
  • xenophagy
  • ER stress
  • mitochondria

1. Autophagy-Related CD Susceptibility Genes

1.1. ATG16L1

ATG16L1 (Autophagy-Related 16 Like 1) was the first identified autophagy-related CD susceptibility gene. ATG16L1 functions as a scaffold protein that helps to assemble the autophagy machinery, and is required for the formation of autophagosomes [1]. The ATG16L1 T300A mutation is associated with an increased risk of developing CD, and several studies have suggested that these mutations may impair autophagy in intestinal epithelial cells and immune cells, contributing to the development of this disease [1]. The T300A variant in ATG16L1 results in aberrant Paneth cell architecture and disordered granularity [2]. Some studies have found that ATG16L1 deficiency leads to impaired autophagy-mediated clearance of intracellular bacteria in intestinal epithelial cells, resulting in increased bacterial load and the activation of inflammatory signaling pathways [1][3]. Further, ATG16L1 mutations reduce the expression of antimicrobial peptides in intestinal epithelial cells, impairing the ability of these cells to defend against pathogenic bacteria [1].

1.2. IRGM

IRGM (Immunity-Related GTPase M) has been shown to interact with components of the autophagy machinery, such as ULK1 and Beclin 1, to promote the formation of autophagosomes in response to infection with intracellular pathogens [3][4][5]. IRGM-deficient mice have impaired clearance of intracellular bacteria in intestinal epithelial cells, leading to increased inflammation and tissue damage [6]. IRGM dampens inflammatory signaling via selective autophagy of the Nucleotide-binding domain, Leucine-rich Repeat-containing Family, and Pyrin Domain Containing 3 (NLRP3) inflammasome, thereby inhibiting its activation and downstream signaling [7]. In addition, IRGM1-deficient mice demonstrate Paneth cell abnormalities and elevated susceptibility to intestinal inflammation [8]. IRGM SNPs rs1000113, rs11747270, rs9637876, rs13361189 and rs180802994 are associated with CD [9]. Some studies have reported that IRGM SNPs may increase fecal lactoferrin (inflammatory biomarker) from the ileum and TNF in whole blood in humans with CD [4]. Further studies are warranted to explore more functional alterations due to IRGM SNPs in CD.

1.3. NOD2

NOD2 (Nucleotide-Binding Oligomerization Domain-Containing Protein 2) encodes a protein involved in the regulation of the immune system and the maintenance of the intestinal barrier function [10][11][12]. NOD2 is an intracellular receptor that recognizes muramyl dipeptide motifs, a component of the bacterial cell wall, and upon activation elicits responses to eradicate invading pathogens including activation of NFκB inflammatory signaling. Recent studies have shown that NOD2 interacts with several proteins involved in autophagy, including ATG16L1 and IRGM, to recruit autophagy machinery to the cellular site of invading bacteria and incorporate bacteria into the forming autophagosome. This has been shown to be important in intestinal epithelial cells at the interface with the gut microbiome [3][13]. Genetic variation in NOD2 accounts for 20% of CD genetic risk, with three common variants, R702W, G908R, and L1007fs, particularly associated with ileal CD [14]. NOD2 mutations impair NFκB and autophagic responses to intracellular bacteria, leading to the accumulation of bacteria in intestinal epithelial cells [15]. NOD2 mutations have also been shown to reduce the expression of ATG16L1 in intestinal epithelial cells as an additional mechanism whereby autophagy-mediated clearance of intracellular bacteria is impaired [16]. Furthermore, NOD2 has been implicated in the Paneth cell-mediated responses against intestinal bacteria-induced inflammation [17].

1.4. LRRK2

LRRK2 (Leucine-Rich Repeat Kinase 2) plays a role in several cellular processes, including autophagy, the immune response, and the regulation of mitochondrial function [18][19]. LRRK2 has been demonstrated to regulate the formation of autophagosomes in intestinal epithelial cells and to maintain functional Paneth cells in CD [20]. LRRK2 plays a role in regulating the formation of autophagosomes by interacting with several proteins involved in this process. One such protein is Rab29, which is a small GTPase that regulates the recruitment of the autophagy-related protein ATG9 to the site of autophagosome formation [21]. In addition, LRRK2 has been shown to phosphorylate Rab29, which enhances its ability to recruit ATG9 to the site of autophagosome formation [21], and to phosphorylate ULK1, enhancing its activity and promoting the initiation of autophagy [22].
Mutations in the LRRK2 gene have been identified as a genetic risk factor for several diseases, including Parkinson’s disease and CD [18][23]. LRRK2 mutations impair the autophagic response to intracellular bacteria in intestinal epithelial cells, leading to an accumulation of bacteria and the activation of inflammatory signaling pathways [24]. In addition to its role in autophagy regulation, LRRK2 has also been shown to regulate the immune response and the expression of several toll-like receptor (TLR)-mediated inflammatory cytokines and chemokines [25]. LRRK2 mutation (M2397T polymorphism), associated with CD, alters CD14+ monocyte-derived type II interferon (IFN) response [26]. Moreover, different variants of LRRK2 are linked to CD and Parkinson’s disease. In CD, the exact mechanisms by which LRRK2 variants contribute to CD pathology are not yet fully understood. However, it is speculated that LRRK2 variants, such as LRRK2 G2019S, may impact immune responses, and intestinal barrier functions, or alter gut microbial composition [27][28][29]. In addition, a mutation in the LRRK2 N2081D allele results in elevated kinase activity while the LRRK2 R1398H variant increases its enzymatic activity altering LRRK2 functionality in CD and Parkinson’s disease [30]. In Parkinson’s disease, several pathogenic LRRK2 variants, such as G2019S and R1441C/G, have been linked to an increased risk of developing this disease [28][31]. These variants are thought to lead to increased LRRK2 kinase activity, which can contribute to neuronal dysfunction and degeneration. Dysregulated kinase activity may affect various cellular processes, including mitochondrial function, protein degradation pathways, and synaptic transmission, ultimately leading to the development of Parkinson’s disease symptoms [31][32].

1.5. ULK1

ULK1 (Unc-51-Like Autophagy Activating Kinase 1) is a protein kinase that plays a critical role in the initiation of autophagy. ULK1 is part of a protein complex known as the ULK1 complex, which also includes ATG13, FIP200, and ATG101 [33]. This complex is activated in response to cellular stress, such as nutrient deprivation or the accumulation of damaged cellular components [33]. Once activated, the ULK1 complex phosphorylates several downstream targets, including the protein Beclin 1, which triggers the formation of autophagosomes [33]. In addition to its role in autophagy initiation, ULK1 also has several other cellular functions, including the regulation of cell growth and differentiation, metabolism, and the response to oxidative stress [34][35][36]. Dysregulation of ULK1 has been implicated in several diseases, including CD, cancer, neurodegenerative disorders, and metabolic disorders [37]. In regards to CD, studies have shown that ULK1 may play a role in regulating the differentiation and function of immune cells [38]. Dysregulation of ULK1 has also been linked to increased intestinal permeability, which can lead to the infiltration of bacteria and other harmful substances into the intestinal tissue, triggering an inflammatory response [39]. The SNP rs12303764 in ULK1 is associated with CD [38].

1.6. ATG4

ATG4 (Autophagy-related protein 4) is a cysteine protease that plays a critical role in the regulation of autophagy via processing of LC3 [40]. Missense variants in ATG4C associated with CD are N75S, R80H, C367Y, K371R, R389X, and a frameshift mutation specifically enriched in Finland (1:62819215:C:CT) [41]. Four of these are truncating variants, suggesting loss-of-function variants in ATG4C increase the risk of CD. Several studies have suggested that dysregulation of ATG4-mediated processing of LC3 may contribute to the development and progression of CD. A study reported that mice lacking ATG4B, one of the isoforms of ATG4, had impaired autophagy and were more susceptible to the development of inflammation [42]. It has also been reported that ATG4B is downregulated in the intestinal mucosa of patients with CD [43], suggesting that dysregulation of ATG4-mediated autophagy may contribute to the development of this disease.

1.7. TCF4

TCF4 (Transcription Factor 4) is a member of the basic helix--loop--helix (bHLH) family of transcription factors that play an important role in the regulation of gene expression and cell survival [44][45]. As a Wnt signaling pathway transcription factor, TCF4 plays an important role in the health of Paneth cells and production of antimicrobial peptides Defensin-5 and Defensin-6 in a Wnt-pathway-dependent manner [46]. TCF4 deficiency leads to impaired autophagy in intestinal epithelial cells, resulting in the accumulation of intracellular bacteria and the activation of inflammatory signaling pathways [47]. SNP rs3814570 in the TCF4 promoter region is associated with ileal CD, with the strongest association in patients with stricturing disease [48].

2. Types of Autophagy Linked to CD Pathogenesis

2.1. Xenophagy

Xenophagy is a specialized form of autophagy that involves the degradation and elimination of invading microorganisms, such as bacteria, viruses, and parasites [49][50]. During xenophagy, the microorganisms are engulfed by an autophagosome and degraded in the autolysosome. Xenophagy is an important innate immune defense mechanism. It is activated by specific cellular receptors, such as TLRs, NOD-like receptors (NLRs), pyrin domain containing 3 (NLRP3), RIG-I-like (RLRs), and C-type receptors (CLRs), that recognize the presence of microbial components, such as bacterial cell wall components or viral nucleic acids [51][52]. TLRs are expressed on the surface of immune cells and basolaterally on intestinal epithelial cells and recognize specific pathogen-associated molecular patterns (PAMPs) on the surface of pathogens. TLR activation triggers downstream signaling cascades that can activate xenophagy and other immune responses [53]. NLRs, including NOD2, are cytosolic pattern recognition receptors that surveil the intracellular environment and activate inflammatory cascades and inflammasomes in response to infection [54][55]. NLRP3 recognizes various PAMPs and danger-associated molecular patterns (DAMPs), including bacterial cell wall components and damaged or dying host cells, respectively [56]. In addition to NLRP3 and TLRs, other receptors involved in xenophagy include RLRs, which recognize viral RNA, and the cGAS-STING pathway, which senses cytosolic DNA. These receptors activate signaling pathways that converge on the autophagy machinery to promote the clearance of invading pathogens and pathogenic DNA [57]. Dysregulation of xenophagy has been linked to various infectious diseases, including tuberculosis, Salmonella infection, and viral infections such as influenza and HIV [52][58].
Xenophagy has been shown to play a critical role in modulating the function of macrophages and DCs in several ways. Xenophagy regulates the production of proinflammatory cytokines, such as interleukin-1 beta (IL-1β), interleukin-6 (IL-6), and tumor necrosis factor-alpha (TNF-α) in macrophages and DCs [59][60]. Xenophagy can regulate inflammasome activation and subsequent IL-1β production by controlling the degradation of bacterial or viral components and regulating the activation of signaling pathways downstream of cytokine receptors in response to bacterial infection [61]. Xenophagy can dampen the production of type I IFNs in response to viral infection by restricting the replication of viral pathogens in infected cells. Conversely, xenophagy can enhance the activation of interferon-stimulated genes (ISGs), including ISG15, UbE1L, UbcH8, and Herc5 [62][63], important for the innate immune response. Xenophagy can modulate cytokine receptor signaling by regulating the turnover of cytokine receptors. For example, xenophagy can mediate the degradation of the interleukin-1 receptor (IL-1R) and the type I IFN receptor (IFNAR), leading to the downregulation of IL-1β and type I IFN signaling, respectively [64]. Xenophagy also plays a critical role in modulating antigen presentation in macrophages and DCs [65]. Xenophagy can facilitate the processing of antigens from intracellular pathogens for presentation on MHC II molecules, leading to the activation of CD4+ T cells [64]. Xenophagy can also regulate the turnover of MHC II molecules, which can impact the efficiency of antigen presentation [66]. Through these mechanisms, xenophagy plays a critical role in modulating functional responses of macrophages and DCs, impacting the innate immune response to intracellular pathogens.
Multiple studies have suggested that defects in xenophagy may contribute to the development and progression of CD. Studies have shown that ATG16L1-, ATG4-, ULK1-deficient mice exhibit defective xenophagy and are more susceptible to bacterial infections in the gut [67][68][69]. Studies have also shown that IRGM expression is reduced in patients with CD [70], and that IRGM-deficient mice exhibit defective xenophagy and are more susceptible to bacterial infections in the gut [8]. In addition, mice lacking IRGM have been shown to exhibit defective Paneth cells accompanied by intestinal injury [71]. Loss of functional mutations in NOD2, associated with CD, result in decreased response to invading bacteria and abnormal immune responses driving chronic intestinal inflammation [54][55]. Mutations in LRRK2 have been associated with an increased risk of developing Parkinson’s disease, and some studies have suggested that LRRK2 may also play a role in regulating xenophagy in the gut [72].

2.2. ERphagy

ERphagy is a selective form of autophagy that involves the degradation of endoplasmic reticulum (ER) by autophagy. The ER is a complex network of interconnected tubules and flattened sacs that plays a critical role in protein synthesis, lipid metabolism, and calcium homeostasis. ERphagy is initiated by the recognition and isolation of a specific region of the ER by a protein called FAM134B, which acts as an ER-phagy receptor [73]. FAM134B binds LC3II and promotes the incorporation of the targeted ER region into an autophagosome that is forming.
ER stress occurs when there is an imbalance between protein folding demand and capacity in the ER [74]. ER stress can be induced by a variety of factors, including inflammation, oxidative stress, and genetic mutations. In CD, chronic inflammation in the intestinal mucosa can induce ER stress in various cells, including Paneth cells and goblet cells [75]. In CD, ER stress in Paneth cells has been shown to impair the secretion of antimicrobial peptides, leading to dysbiosis and increased susceptibility to bacterial infections [2][76]. Similarly, ER stress in goblet cells has been shown to impair mucus secretion and increase susceptibility to bacterial adhesion and invasion in CD [76][77]. The unfolded protein response (UPR) is a cellular stress response pathway that is activated in response to ER stress [78]. The UPR is initiated by three transmembrane proteins: PERK, ATF6, and IRE1. In CD, the UPR pathway is activated in Paneth cells and goblet cells, leading to increased expression of genes in humans (HSPA5 encoding BIP/HSP70, DERL1, EDEM, ATF6, XBP1, and IRE1) that are involved in protein folding, degradation, and secretion [75].
ERphagy plays an important role in dampening ER stress and maintaining ER homeostasis by removing damaged or excess ER. Dysfunction of ERphagy has been implicated in several diseases, including CD, neurodegenerative disorders, and cancer [79][80]. ERphagy is regulated by several key proteins, including X-box binding protein 1 (XBP1) and ATG16L1 [81][82]. XBP1 is a transcription factor that regulates the expression of genes involved in protein folding, secretion, ER stress response, and UPR [83][84]. Dysregulation of the UPR has been implicated in the pathogenesis of CD [85], and studies have suggested that XBP1 plays a role in the regulation of autophagy in response to ER stress [86]. Mice with deletion of Xbp1 in the intestinal epithelium (Xbp1ΔIEC) developed ER stress, Paneth cell impairment, and mild-to-moderate spontaneous ileitis [87]. Loss of autophagy via crossing to mice with deletion of Atg7 in the intestinal epithelial cells (Atg7/Xbp1ΔIEC), resulted in unresolved ER stress and a worsening of ileitis compared to Xbp1ΔIEC mice [87]. Later studies demonstrated that prolonged activation of the UPR driving accumulation of IRE1α aggregates contributed to the development of transmural ileitis when not dampened by autophagy [88]. Studies have shown that XBP1 plays a role in the regulation of ERphagy by promoting the expression of FAM134B, the ERphagy receptor, and that ATG16L1 interacts with FAM134B and promotes ERphagy [81][89]. Similar to Paneth cells, impairment of ERphagy in mice by ATG16L1, IRGM1, or NOD2 deficiency results in goblet cell mucus secretion defects and compromised barrier function [8][77][90]. ER stress unresolved by ERphagy may be especially deleterious in intestinal secretory cells, such as Paneth cells or goblet cells, due to their high reliance on ER for their protein secretory functions.

2.3. Mitophagy

Mitophagy is a specialized form of autophagy that involves the selective degradation and recycling of damaged or dysfunctional mitochondria, the energy-producing (ATP) organelles within cells. Damaged or dysfunctional mitochondria can produce harmful reactive oxygen species and contribute to cellular dysfunction and disease [91]. During mitophagy, mitochondria are targeted for degradation by specific receptors, such as Nix/Bnip3L or PINK1 recruitment of Parkin, and engulfed by the autophagosome. Dysregulation of mitophagy has been linked to various diseases, including neurodegenerative disorders, IBD, cancer, and metabolic disorders [92][93][94].
Similar to ER stress, studies investigating mitochondrial stress in the intestine have revealed the role of mitochondrial health as being crucial to Paneth cell health and functionality. A recent study induced intestinal epithelial cell-specific mitochondrial dysfunction via deletion of the mitochondrial chaperone protein Prohibitin 1 [95]. The mice developed spontaneous ileitis that was preceded by mitochondrial dysfunction in all epithelial cells, crypt cell death, and defects in Paneth cells. Importantly, IBD patients exhibit intestinal epithelial mitochondrial dysfunction and decreased expression of PHB1 [93]. Paneth cell abnormalities, including loss of antimicrobial peptide expression, and ileitis could be ameliorated in PHB1 deficient mice by the administration of a mitochondrial-targeted antioxidant, Mito-Tempo, suggesting that mitochondrial reactive oxygen species contributed to disease progression in this model of intestinal epithelial cell mitochondrial dysfunction [95]. A specific role of Paneth cell mitochondrial dysfunction in driving ileitis was demonstrated using mice with Paneth cell-specific deletion of PHB1 [95]. Further studies in these mice revealed a loss of Nix/Bnip3L-mediated mitophagy in the intestinal epithelium during PHB1 deficiency [96], suggesting mitochondrial dysfunction coupled with inefficient removal by mitophagy.
Collectively, these results identify Paneth cells as highly susceptible to mitochondrial dysfunction. Deficiency in Atg16L1, Atg7, Atg5, or Irgm1 in mice causes Paneth cell defects and CD autophagy-related susceptibility genes, or their disease-linked variants (ATG16L1 T300A, LRRK2, IRGM), are associated with Paneth cell abnormalities in the ileum [97][98][99]. Recent studies demonstrated mitochondrial impairment in abnormal CD Paneth cells that correlated with ATG16L1 T300A mutation [100]. Furthermore, LRRK2 serves as a significant risk factor for both Parkinson’s and Crohn’s disease, conditions associated with impairments in mitophagy and/or mitochondrial health [28]. Mitochondrial health may be especially important in Paneth cells due to their long-lived nature (30–60 days), compared to other intestinal epithelial cells [101], and their extensive ER for secretory functions coupled with the known communication between mitochondria and ER [102]. Future studies are needed to fully understand the complex interplay between mitochondria and ER in the intestine during health and disease and how it impacts specific epithelial and immune cell types.

This entry is adapted from the peer-reviewed paper 10.3390/cells12131779

References

  1. Henderson, P.; Stevens, C. The role of autophagy in Crohn’s disease. Cells 2012, 1, 492–519.
  2. Deuring, J.J.; Fuhler, G.M.; Konstantinov, S.R.; Peppelenbosch, M.P.; Kuipers, E.J.; de Haar, C.; van der Woude, C.J. Genomic ATG16L1 risk allele-restricted Paneth cell ER stress in quiescent Crohn’s disease. Gut 2014, 63, 1081–1091.
  3. Shao, B.Z.; Yao, Y.; Zhai, J.S.; Zhu, J.H.; Li, J.P.; Wu, K. The Role of Autophagy in Inflammatory Bowel Disease. Front. Physiol. 2021, 12, 621132.
  4. Ajayi, T.A.; Innes, C.L.; Grimm, S.A.; Rai, P.; Finethy, R.; Coers, J.; Wang, X.; Bell, D.A.; McGrath, J.A.; Schurman, S.H.; et al. Crohn’s disease IRGM risk alleles are associated with altered gene expression in human tissues. Am. J. Physiol. Gastrointest. Liver Physiol. 2019, 316, G95–G105.
  5. Chauhan, S.; Mandell, M.A.; Deretic, V. IRGM governs the core autophagy machinery to conduct antimicrobial defense. Mol. Cell. 2015, 58, 507–521.
  6. Taylor, G.A.; Huang, H.I.; Fee, B.E.; Youssef, N.; Jewell, M.L.; Cantillana, V.; Schoenborn, A.A.; Rogala, A.R.; Buckley, A.F.; Feng, C.G.; et al. Irgm1-deficiency leads to myeloid dysfunction in colon lamina propria and susceptibility to the intestinal pathogen Citrobacter rodentium. PLoS Pathog. 2020, 16, e1008553.
  7. Mehto, S.; Jena, K.K.; Nath, P.; Chauhan, S.; Kolapalli, S.P.; Das, S.K.; Sahoo, P.K.; Jain, A.; Taylor, G.A.; Chauhan, S. The Crohn’s Disease Risk Factor IRGM Limits NLRP3 Inflammasome Activation by Impeding Its Assembly and by Mediating Its Selective Autophagy. Mol. Cell 2019, 73, 429–445.e7.
  8. Liu, B.; Gulati, A.S.; Cantillana, V.; Henry, S.C.; Schmidt, E.A.; Daniell, X.; Grossniklaus, E.; Schoenborn, A.A.; Sartor, R.B.; Taylor, G.A. Irgm1-deficient mice exhibit Paneth cell abnormalities and increased susceptibility to acute intestinal inflammation. Am. J. Physiol. Gastrointest. Liver Physiol. 2013, 305, G573–G584.
  9. Baskaran, K.; Pugazhendhi, S.; Ramakrishna, B.S. Association of IRGM gene mutations with inflammatory bowel disease in the Indian population. PLoS ONE 2014, 9, e106863.
  10. Al Nabhani, Z.; Dietrich, G.; Hugot, J.P.; Barreau, F. Nod2: The intestinal gate keeper. PLoS Pathog. 2017, 13, e1006177.
  11. Liu, Z.; Zhang, Y.; Jin, T.; Yi, C.; Ocansey, D.K.W.; Mao, F. The role of NOD2 in intestinal immune response and microbiota modulation: A therapeutic target in inflammatory bowel disease. Int. Immunopharmacol. 2022, 113, 109466.
  12. Hall, L.J.; Watson, A.J. Role of autophagy in NOD2-induced inflammation in Crohn’s disease. Gastroenterology 2012, 142, 1032–1034.
  13. Fritz, T.; Niederreiter, L.; Adolph, T.; Blumberg, R.S.; Kaser, A. Crohn’s disease: NOD2, autophagy and ER stress converge. Gut 2011, 60, 1580–1588.
  14. Lesage, S.; Zouali, H.; Cezard, J.P.; Colombel, J.F.; Belaiche, J.; Almer, S.; Tysk, C.; O’Morain, C.; Gassull, M.; Binder, V.; et al. CARD15/NOD2 mutational analysis and genotype-phenotype correlation in 612 patients with inflammatory bowel disease. Am. J. Hum. Genet. 2002, 70, 845–857.
  15. Sidiq, T.; Yoshihama, S.; Downs, I.; Kobayashi, K.S. Nod2: A Critical Regulator of Ileal Microbiota and Crohn’s Disease. Front. Immunol. 2016, 7, 367.
  16. Travassos, L.H.; Carneiro, L.A.; Ramjeet, M.; Hussey, S.; Kim, Y.G.; Magalhaes, J.G.; Yuan, L.; Soares, F.; Chea, E.; Le Bourhis, L.; et al. Nod1 and Nod2 direct autophagy by recruiting ATG16L1 to the plasma membrane at the site of bacterial entry. Nat. Immunol. 2010, 11, 55–62.
  17. Ogura, Y.; Lala, S.; Xin, W.; Smith, E.; Dowds, T.A.; Chen, F.F.; Zimmermann, E.; Tretiakova, M.; Cho, J.H.; Hart, J.; et al. Expression of NOD2 in Paneth cells: A possible link to Crohn’s ileitis. Gut 2003, 52, 1591–1597.
  18. Liu, Z.; Lenardo, M.J. The role of LRRK2 in inflammatory bowel disease. Cell. Res. 2012, 22, 1092–1094.
  19. Singh, A.; Zhi, L.; Zhang, H. LRRK2 and mitochondria: Recent advances and current views. Brain Res. 2019, 1702, 96–104.
  20. Yang, E.; Shen, J. The roles and functions of Paneth cells in Crohn’s disease: A critical review. Cell. Prolif. 2021, 54, e12958.
  21. Boecker, C.A.; Goldsmith, J.; Dou, D.; Cajka, G.G.; Holzbaur, E.L.F. Increased LRRK2 kinase activity alters neuronal autophagy by disrupting the axonal transport of autophagosomes. Curr. Biol. 2021, 31, 2140–2154.e6.
  22. Manzoni, C.; Mamais, A.; Dihanich, S.; Soutar, M.P.M.; Plun-Favreau, H.; Bandopadhyay, R.; Abeti, R.; Giunti, P.; Hardy, J.; Cookson, M.R.; et al. mTOR independent alteration in ULK1 Ser758 phosphorylation following chronic LRRK2 kinase inhibition. Biosci. Rep. 2018, 38, BSR20171669.
  23. Rocha, E.M.; Keeney, M.T.; Di Maio, R.; De Miranda, B.R.; Greenamyre, J.T. LRRK2 and idiopathic Parkinson’s disease. Trends Neurosci. 2022, 45, 224–236.
  24. Wallings, R.L.; Tansey, M.G. LRRK2 regulation of immune-pathways and inflammatory disease. Biochem. Soc. Trans. 2019, 47, 1581–1595.
  25. Ahmadi Rastegar, D.; Hughes, L.P.; Perera, G.; Keshiya, S.; Zhong, S.; Gao, J.; Halliday, G.M.; Schule, B.; Dzamko, N. Effect of LRRK2 protein and activity on stimulated cytokines in human monocytes and macrophages. NPJ Park. Dis. 2022, 8, 34.
  26. Ikezu, T.; Koro, L.; Wolozin, B.; Farraye, F.A.; Strongosky, A.J.; Wszolek, Z.K. Crohn’s and Parkinson’s Disease-Associated LRRK2 Mutations Alter Type II Interferon Responses in Human CD14+ Blood Monocytes Ex Vivo. J. Neuroimmune Pharm. 2020, 15, 794–800.
  27. Park, J.; Lee, J.W.; Cooper, S.C.; Broxmeyer, H.E.; Cannon, J.R.; Kim, C.H. Parkinson disease-associated LRRK2 G2019S transgene disrupts marrow myelopoiesis and peripheral Th17 response. J. Leukoc. Biol. 2017, 102, 1093–1102.
  28. Herrick, M.K.; Tansey, M.G. Is LRRK2 the missing link between inflammatory bowel disease and Parkinson’s disease? NPJ Park. Dis. 2021, 7, 26.
  29. Shutinoski, B.; Hakimi, M.; Harmsen, I.E.; Lunn, M.; Rocha, J.; Lengacher, N.; Zhou, Y.Y.; Khan, J.; Nguyen, A.; Hake-Volling, Q.; et al. Lrrk2 alleles modulate inflammation during microbial infection of mice in a sex-dependent manner. Sci. Transl. Med. 2019, 11, eaas9292.
  30. Hui, K.Y.; Fernandez-Hernandez, H.; Hu, J.; Schaffner, A.; Pankratz, N.; Hsu, N.Y.; Chuang, L.S.; Carmi, S.; Villaverde, N.; Li, X.; et al. Functional variants in the LRRK2 gene confer shared effects on risk for Crohn’s disease and Parkinson’s disease. Sci. Transl. Med. 2018, 10, eaai7795.
  31. Benson, D.L.; Matikainen-Ankney, B.A.; Hussein, A.; Huntley, G.W. Functional and behavioral consequences of Parkinson’s disease-associated LRRK2-G2019S mutation. Biochem. Soc. Trans. 2018, 46, 1697–1705.
  32. Usmani, A.; Shavarebi, F.; Hiniker, A. The Cell Biology of LRRK2 in Parkinson’s Disease. Mol. Cell. Biol. 2021, 41, e00660-20.
  33. Zachari, M.; Ganley, I.G. The mammalian ULK1 complex and autophagy initiation. Essays Biochem. 2017, 61, 585–596.
  34. Ianniciello, A.; Zarou, M.M.; Rattigan, K.M.; Scott, M.; Dawson, A.; Dunn, K.; Brabcova, Z.; Kalkman, E.R.; Nixon, C.; Michie, A.M.; et al. ULK1 inhibition promotes oxidative stress-induced differentiation and sensitizes leukemic stem cells to targeted therapy. Sci. Transl. Med. 2021, 13, eabd5016.
  35. Ro, S.H.; Jung, C.H.; Hahn, W.S.; Xu, X.; Kim, Y.M.; Yun, Y.S.; Park, J.M.; Kim, K.H.; Seo, M.; Ha, T.Y.; et al. Distinct functions of Ulk1 and Ulk2 in the regulation of lipid metabolism in adipocytes. Autophagy 2013, 9, 2103–2114.
  36. Jung, C.H.; Seo, M.; Otto, N.M.; Kim, D.H. ULK1 inhibits the kinase activity of mTORC1 and cell proliferation. Autophagy 2011, 7, 1212–1221.
  37. Morgan, A.R.; Lam, W.J.; Han, D.Y.; Fraser, A.G.; Ferguson, L.R. Association Analysis of ULK1 with Crohn’s Disease in a New Zealand Population. Gastroenterol. Res. Pract. 2012, 2012, 715309.
  38. Henckaerts, L.; Cleynen, I.; Brinar, M.; John, J.M.; Van Steen, K.; Rutgeerts, P.; Vermeire, S. Genetic variation in the autophagy gene ULK1 and risk of Crohn’s disease. Inflamm. Bowel Dis. 2011, 17, 1392–1397.
  39. Radhi, O.A.; Davidson, S.; Scott, F.; Zeng, R.X.; Jones, D.H.; Tomkinson, N.C.O.; Yu, J.; Chan, E.Y.W. Inhibition of the ULK1 protein complex suppresses Staphylococcus-induced autophagy and cell death. J. Biol. Chem. 2019, 294, 14289–14307.
  40. Yang, A.; Pantoom, S.; Wu, Y.W. Distinct Mechanisms for Processing Autophagy Protein LC3-PE by RavZ and ATG4B. ChemBioChem 2020, 21, 3377–3382.
  41. Sazonovs, A.; Stevens, C.R.; Venkataraman, G.R.; Yuan, K.; Avila, B.; Abreu, M.T.; Ahmad, T.; Allez, M.; Ananthakrishnan, A.N.; Atzmon, G.; et al. Large-scale sequencing identifies multiple genes and rare variants associated with Crohn’s disease susceptibility. Nat. Genet. 2022, 54, 1275–1283.
  42. Fernandez, A.F.; Lopez-Otin, C. The functional and pathologic relevance of autophagy proteases. J. Clin. Investig. 2015, 125, 33–41.
  43. Li, Z.; Wang, G.; Feng, D.; Zu, G.; Li, Y.; Shi, X.; Zhao, Y.; Jing, H.; Ning, S.; Le, W.; et al. Targeting the miR-665-3p-ATG4B-autophagy axis relieves inflammation and apoptosis in intestinal ischemia/reperfusion. Cell. Death Dis. 2018, 9, 483.
  44. Papes, F.; Camargo, A.P.; de Souza, J.S.; Carvalho, V.M.A.; Szeto, R.A.; LaMontagne, E.; Teixeira, J.R.; Avansini, S.H.; Sanchez-Sanchez, S.M.; Nakahara, T.S.; et al. Transcription Factor 4 loss-of-function is associated with deficits in progenitor proliferation and cortical neuron content. Nat. Commun. 2022, 13, 2387.
  45. Forrest, M.P.; Waite, A.J.; Martin-Rendon, E.; Blake, D.J. Knockdown of human TCF4 affects multiple signaling pathways involved in cell survival, epithelial to mesenchymal transition and neuronal differentiation. PLoS ONE 2013, 8, e73169.
  46. Wehkamp, J.; Wang, G.; Kubler, I.; Nuding, S.; Gregorieff, A.; Schnabel, A.; Kays, R.J.; Fellermann, K.; Burk, O.; Schwab, M.; et al. The Paneth cell alpha-defensin deficiency of ileal Crohn’s disease is linked to Wnt/Tcf-4. J. Immunol. 2007, 179, 3109–3118.
  47. Gersemann, M.; Wehkamp, J.; Fellermann, K.; Stange, E.F. Crohn’s disease—Defect in innate defence. World J. Gastroenterol. 2008, 14, 5499–5503.
  48. Koslowski, M.J.; Kubler, I.; Chamaillard, M.; Schaeffeler, E.; Reinisch, W.; Wang, G.; Beisner, J.; Teml, A.; Peyrin-Biroulet, L.; Winter, S.; et al. Genetic variants of Wnt transcription factor TCF-4 (TCF7L2) putative promoter region are associated with small intestinal Crohn’s disease. PLoS ONE 2009, 4, e4496.
  49. Chaudhary, A.; Miller, S.I. Xenophagy: Pathogen-Containing Vacuoles Are Hard to Digest. Curr. Biol. 2019, 29, R1086–R1088.
  50. Bauckman, K.A.; Owusu-Boaitey, N.; Mysorekar, I.U. Selective autophagy: Xenophagy. Methods 2015, 75, 120–127.
  51. Knodler, L.A.; Celli, J. Eating the strangers within: Host control of intracellular bacteria via xenophagy. Cell. Microbiol. 2011, 13, 1319–1327.
  52. Chen, T.; Tu, S.; Ding, L.; Jin, M.; Chen, H.; Zhou, H. The role of autophagy in viral infections. J. Biomed. Sci. 2023, 30, 5.
  53. Shao, Y.; Wang, Z.; Chen, K.; Li, D.; Lv, Z.; Zhang, C.; Zhang, W.; Li, C. Xenophagy of invasive bacteria is differentially activated and modulated via a TLR-TRAF6-Beclin1 axis in echinoderms. J. Biol. Chem. 2022, 298, 101667.
  54. Shaw, M.H.; Kamada, N.; Warner, N.; Kim, Y.G.; Nunez, G. The ever-expanding function of NOD2: Autophagy, viral recognition, and T cell activation. Trends Immunol. 2011, 32, 73–79.
  55. Brain, O.; Allan, P.; Simmons, A. NOD2-mediated autophagy and Crohn disease. Autophagy 2010, 6, 412–414.
  56. Biasizzo, M.; Kopitar-Jerala, N. Interplay Between NLRP3 Inflammasome and Autophagy. Front. Immunol. 2020, 11, 591803.
  57. Paulus, G.L.; Xavier, R.J. Autophagy and checkpoints for intracellular pathogen defense. Curr. Opin. Gastroenterol. 2015, 31, 14–23.
  58. Sharma, V.; Verma, S.; Seranova, E.; Sarkar, S.; Kumar, D. Selective Autophagy and Xenophagy in Infection and Disease. Front. Cell Dev. Biol. 2018, 6, 147.
  59. Lapaquette, P.; Bringer, M.A.; Darfeuille-Michaud, A. Defects in autophagy favour adherent-invasive Escherichia coli persistence within macrophages leading to increased pro-inflammatory response. Cell. Microbiol. 2012, 14, 791–807.
  60. Silwal, P.; Kim, J.K.; Jeon, S.M.; Lee, J.Y.; Kim, Y.J.; Kim, Y.S.; Seo, Y.; Kim, J.; Kim, S.Y.; Lee, M.J.; et al. Mitofusin-2 boosts innate immunity through the maintenance of aerobic glycolysis and activation of xenophagy in mice. Commun. Biol. 2021, 4, 548.
  61. Bah, A.; Vergne, I. Macrophage Autophagy and Bacterial Infections. Front. Immunol. 2017, 8, 1483.
  62. Nakashima, H.; Nguyen, T.; Goins, W.F.; Chiocca, E.A. Interferon-stimulated gene 15 (ISG15) and ISG15-linked proteins can associate with members of the selective autophagic process, histone deacetylase 6 (HDAC6) and SQSTM1/p62. J. Biol. Chem. 2015, 290, 1485–1495.
  63. Bhushan, J.; Radke, J.B.; Perng, Y.C.; McAllaster, M.; Lenschow, D.J.; Virgin, H.W.; Sibley, L.D. ISG15 Connects Autophagy and IFN-gamma-Dependent Control of Toxoplasma gondii Infection in Human Cells. mBio 2020, 11, e00852-20.
  64. Germic, N.; Frangez, Z.; Yousefi, S.; Simon, H.U. Regulation of the innate immune system by autophagy: Monocytes, macrophages, dendritic cells and antigen presentation. Cell Death Differ. 2019, 26, 715–727.
  65. Germic, N.; Frangez, Z.; Yousefi, S.; Simon, H.U. Regulation of the innate immune system by autophagy: Neutrophils, eosinophils, mast cells, NK cells. Cell Death Differ. 2019, 26, 703–714.
  66. Gradzka, S.; Thomas, O.S.; Kretz, O.; Haimovici, A.; Vasilikos, L.; Wong, W.W.; Hacker, G.; Gentle, I.E. Inhibitor of apoptosis proteins are required for effective fusion of autophagosomes with lysosomes. Cell Death Dis. 2018, 9, 529.
  67. Cabrera, S.; Fernandez, A.F.; Marino, G.; Aguirre, A.; Suarez, M.F.; Espanol, Y.; Vega, J.A.; Laura, R.; Fueyo, A.; Fernandez-Garcia, M.S.; et al. ATG4B/autophagin-1 regulates intestinal homeostasis and protects mice from experimental colitis. Autophagy 2013, 9, 1188–1200.
  68. Alsaadi, R.M.; Losier, T.T.; Tian, W.; Jackson, A.; Guo, Z.; Rubinsztein, D.C.; Russell, R.C. ULK1-mediated phosphorylation of ATG16L1 promotes xenophagy, but destabilizes the ATG16L1 Crohn’s mutant. EMBO Rep. 2019, 20, e46885.
  69. Marchiando, A.M.; Ramanan, D.; Ding, Y.; Gomez, L.E.; Hubbard-Lucey, V.M.; Maurer, K.; Wang, C.; Ziel, J.W.; van Rooijen, N.; Nunez, G.; et al. A deficiency in the autophagy gene Atg16L1 enhances resistance to enteric bacterial infection. Cell Host Microbe 2013, 14, 216–224.
  70. Brest, P.; Lapaquette, P.; Souidi, M.; Lebrigand, K.; Cesaro, A.; Vouret-Craviari, V.; Mari, B.; Barbry, P.; Mosnier, J.F.; Hebuterne, X.; et al. A synonymous variant in IRGM alters a binding site for miR-196 and causes deregulation of IRGM-dependent xenophagy in Crohn’s disease. Nat. Genet. 2011, 43, 242–245.
  71. Rogala, A.R.; Schoenborn, A.A.; Fee, B.E.; Cantillana, V.A.; Joyce, M.J.; Gharaibeh, R.Z.; Roy, S.; Fodor, A.A.; Sartor, R.B.; Taylor, G.A.; et al. Environmental factors regulate Paneth cell phenotype and host susceptibility to intestinal inflammation in Irgm1-deficient mice. Dis. Model. Mech. 2018, 11, dmm031070.
  72. Kim, S.; Eun, H.S.; Jo, E.K. Roles of Autophagy-Related Genes in the Pathogenesis of Inflammatory Bowel Disease. Cells 2019, 8, 77.
  73. Mochida, K.; Nakatogawa, H. ER-phagy: Selective autophagy of the endoplasmic reticulum. EMBO Rep. 2022, 23, e55192.
  74. Lin, J.H.; Walter, P.; Yen, T.S. Endoplasmic reticulum stress in disease pathogenesis. Annu. Rev. Pathol. 2008, 3, 399–425.
  75. Hosomi, S.; Kaser, A.; Blumberg, R.S. Role of endoplasmic reticulum stress and autophagy as interlinking pathways in the pathogenesis of inflammatory bowel disease. Curr. Opin. Gastroenterol. 2015, 31, 81–88.
  76. Kaser, A.; Blumberg, R.S. Endoplasmic reticulum stress and intestinal inflammation. Mucosal Immunol. 2010, 3, 11–16.
  77. Naama, M.; Telpaz, S.; Awad, A.; Ben-Simon, S.; Harshuk-Shabso, S.; Modilevsky, S.; Rubin, E.; Sawaed, J.; Zelik, L.; Zigdon, M.; et al. Autophagy controls mucus secretion from intestinal goblet cells by alleviating ER stress. Cell Host Microbe 2023, 31, 433–446.e4.
  78. Amen, O.M.; Sarker, S.D.; Ghildyal, R.; Arya, A. Endoplasmic Reticulum Stress Activates Unfolded Protein Response Signaling and Mediates Inflammation, Obesity, and Cardiac Dysfunction: Therapeutic and Molecular Approach. Front. Pharm. 2019, 10, 977.
  79. Tschurtschenthaler, M.; Adolph, T.E. The Selective Autophagy Receptor Optineurin in Crohn’s Disease. Front. Immunol. 2018, 9, 766.
  80. He, L.; Qian, X.; Cui, Y. Advances in ER-Phagy and Its Diseases Relevance. Cells 2021, 10, 2328.
  81. Aden, K.; Tran, F.; Ito, G.; Sheibani-Tezerji, R.; Lipinski, S.; Kuiper, J.W.; Tschurtschenthaler, M.; Saveljeva, S.; Bhattacharyya, J.; Hasler, R.; et al. ATG16L1 orchestrates interleukin-22 signaling in the intestinal epithelium via cGAS-STING. J. Exp. Med. 2018, 215, 2868–2886.
  82. Stengel, S.T.; Fazio, A.; Lipinski, S.; Jahn, M.T.; Aden, K.; Ito, G.; Wottawa, F.; Kuiper, J.W.P.; Coleman, O.I.; Tran, F.; et al. Activating Transcription Factor 6 Mediates Inflammatory Signals in Intestinal Epithelial Cells Upon Endoplasmic Reticulum Stress. Gastroenterology 2020, 159, 1357–1374.e10.
  83. Chipurupalli, S.; Samavedam, U.; Robinson, N. Crosstalk Between ER Stress, Autophagy and Inflammation. Front. Med. 2021, 8, 758311.
  84. Kamimura, D.; Bevan, M.J. Endoplasmic reticulum stress regulator XBP-1 contributes to effector CD8+ T cell differentiation during acute infection. J. Immunol. 2008, 181, 5433–5441.
  85. Kaser, A.; Adolph, T.E.; Blumberg, R.S. The unfolded protein response and gastrointestinal disease. Semin. Immunopathol. 2013, 35, 307–319.
  86. Margariti, A.; Li, H.; Chen, T.; Martin, D.; Vizcay-Barrena, G.; Alam, S.; Karamariti, E.; Xiao, Q.; Zampetaki, A.; Zhang, Z.; et al. XBP1 mRNA splicing triggers an autophagic response in endothelial cells through BECLIN-1 transcriptional activation. J. Biol. Chem. 2013, 288, 859–872.
  87. Adolph, T.E.; Tomczak, M.F.; Niederreiter, L.; Ko, H.J.; Bock, J.; Martinez-Naves, E.; Glickman, J.N.; Tschurtschenthaler, M.; Hartwig, J.; Hosomi, S.; et al. Paneth cells as a site of origin for intestinal inflammation. Nature 2013, 503, 272–276.
  88. Tschurtschenthaler, M.; Adolph, T.E.; Ashcroft, J.W.; Niederreiter, L.; Bharti, R.; Saveljeva, S.; Bhattacharyya, J.; Flak, M.B.; Shih, D.Q.; Fuhler, G.M.; et al. Defective ATG16L1-mediated removal of IRE1alpha drives Crohn’s disease-like ileitis. J. Exp. Med. 2017, 214, 401–422.
  89. Zhou, H.; Wang, K.; Wang, M.; Zhao, W.; Zhang, C.; Cai, M.; Qiu, Y.; Zhang, T.; Shao, R.; Zhao, W. ER-phagy in the Occurrence and Development of Cancer. Biomedicines 2022, 10, 707.
  90. Matsuzawa-Ishimoto, Y.; Shono, Y.; Gomez, L.E.; Hubbard-Lucey, V.M.; Cammer, M.; Neil, J.; Dewan, M.Z.; Lieberman, S.R.; Lazrak, A.; Marinis, J.M.; et al. Autophagy protein ATG16L1 prevents necroptosis in the intestinal epithelium. J. Exp. Med. 2017, 214, 3687–3705.
  91. Zorov, D.B.; Juhaszova, M.; Sollott, S.J. Mitochondrial reactive oxygen species (ROS) and ROS-induced ROS release. Physiol. Rev. 2014, 94, 909–950.
  92. Doblado, L.; Lueck, C.; Rey, C.; Samhan-Arias, A.K.; Prieto, I.; Stacchiotti, A.; Monsalve, M. Mitophagy in Human Diseases. Int. J. Mol. Sci. 2021, 22, 3903.
  93. Ho, G.T.; Theiss, A.L. Mitochondria and Inflammatory Bowel Diseases: Toward a Stratified Therapeutic Intervention. Annu. Rev. Physiol. 2022, 84, 435–459.
  94. Zhang, L.; Dai, L.; Li, D. Mitophagy in neurological disorders. J. Neuroinflammation 2021, 18, 297.
  95. Jackson, D.N.; Panopoulos, M.; Neumann, W.L.; Turner, K.; Cantarel, B.L.; Thompson-Snipes, L.; Dassopoulos, T.; Feagins, L.A.; Souza, R.F.; Mills, J.C.; et al. Mitochondrial dysfunction during loss of prohibitin 1 triggers Paneth cell defects and ileitis. Gut 2020, 69, 1928–1938.
  96. Alula, K.M.; Delgado-Deida, Y.; Callahan, R.; Till, A.; Underwood, L.; Thompson, W.E.; Souza, R.F.; Dassopoulos, T.; Onyiah, J.; Venuprasad, K.; et al. Inner mitochondrial membrane protein Prohibitin 1 mediates Nix-induced, Parkin-independent mitophagy. Sci. Rep. 2023, 13, 18.
  97. Liu, T.C.; Gao, F.; McGovern, D.P.; Stappenbeck, T.S. Spatial and temporal stability of paneth cell phenotypes in Crohn’s disease: Implications for prognostic cellular biomarker development. Inflamm. Bowel Dis. 2014, 20, 646–651.
  98. Liu, T.C.; Gurram, B.; Baldridge, M.T.; Head, R.; Lam, V.; Luo, C.; Cao, Y.; Simpson, P.; Hayward, M.; Holtz, M.L.; et al. Paneth cell defects in Crohn’s disease patients promote dysbiosis. JCI Insight 2016, 1, e86907.
  99. Liu, T.C.; Kern, J.T.; VanDussen, K.L.; Xiong, S.; Kaiko, G.E.; Wilen, C.B.; Rajala, M.W.; Caruso, R.; Holtzman, M.J.; Gao, F.; et al. Interaction between smoking and ATG16L1T300A triggers Paneth cell defects in Crohn’s disease. J. Clin. Investig. 2018, 128, 5110–5122.
  100. Alula, K.M.; Jackson, D.N.; Smith, A.D.; Kim, D.S.; Turner, K.; Odstrcil, E.; Kaipparettu, B.A.; Dassopoulos, T.; Venuprasad, K.; Feagins, L.A.; et al. Targeting Mitochondrial Damage as a Therapeutic for Ileal Crohn’s Disease. Cells 2021, 10, 1349.
  101. Clevers, H.C.; Bevins, C.L. Paneth cells: Maestros of the small intestinal crypts. Annu. Rev. Physiol. 2013, 75, 289–311.
  102. Mao, H.; Chen, W.; Chen, L.; Li, L. Potential role of mitochondria-associated endoplasmic reticulum membrane proteins in diseases. Biochem. Pharm. 2022, 199, 115011.
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