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• W2024134629 abstract "Crohn's disease is a chronic inflammatory bowel disorder that has been associated with polymorphisms in the genes encoding the pattern-recognition receptor NOD2 and the autophagic regulator ATG16L1. A new study demonstrates that NOD2 recruits ATG16L1 at bacterial entry sites, thereby bridging innate immunity and autophagy. Crohn's disease is a chronic inflammatory bowel disorder that has been associated with polymorphisms in the genes encoding the pattern-recognition receptor NOD2 and the autophagic regulator ATG16L1. A new study demonstrates that NOD2 recruits ATG16L1 at bacterial entry sites, thereby bridging innate immunity and autophagy. The etiology of chronic inflammatory disorders of the bowel, such as Crohn's disease, is largely unknown; however, recent epidemiological studies have suggested the existence of a strong genetic predisposition interacting with hitherto undetermined environmental triggers to render susceptible individuals at risk. More than 30 distinct loci have indeed been involved in the genetic susceptibility to Crohn's disease, including genes implicated in autophagy, maintenance of epithelial barrier integrity, innate immunity, and secondary immune responses [1Van Limbergen J. Wilson D.C. Satsangi J. The genetics of Crohn's disease.Annu. Rev. Genomics Hum. Genet. 2009; 10: 89-116Crossref PubMed Scopus (194) Google Scholar]. In particular, Crohn's disease has been associated with polymorphisms affecting the essential autophagic modulator ATG16L1 and the pattern-recognition receptor (PRR) NOD2 [2Levine B. Kroemer G. Autophagy in the pathogenesis of disease.Cell. 2008; 132: 27-42Abstract Full Text Full Text PDF PubMed Scopus (4973) Google Scholar]. Although both ATG16L1 and NOD2 had previously been shown to be required for the proper recognition and disposal of intracellular pathogens (including enteric bacteria that may contribute to the etiology of Crohn's disease) [3Inohara N. Ogura Y. Fontalba A. Gutierrez O. Pons F. Crespo J. Fukase K. Inamura S. Kusumoto S. Hashimoto M. et al.Host recognition of bacterial muramyl dipeptide mediated through NOD2. Implications for Crohn's disease.J. Biol. Chem. 2003; 278: 5509-5512Crossref PubMed Scopus (1346) Google Scholar, 4Kuballa P. Huett A. Rioux J.D. Daly M.J. Xavier R.J. Impaired autophagy of an intracellular pathogen induced by a Crohn's disease associated ATG16L1 variant.PLoS ONE. 2008; 3: e3391Crossref PubMed Scopus (269) Google Scholar], until recently a mechanistic link between these proteins was missing. Now, Travassos et al. [5Travassos 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. 2009; 11: 55-62Crossref PubMed Scopus (938) Google Scholar] have demonstrated that NOD2 recruits ATG16L1 at the plasma membrane of infected cells to activate the generation of autophagosomes around invading bacteria, thereby pointing to a functional link between autophagy and innate immunity that is critical for the etiology of Crohn's disease. Autophagy is a finely regulated, evolutionarily conserved multi-step process by which damaged, supernumerary or ectopic intracellular entities are sent to lysosomes for degradation [6Galluzzi L. Vicencio J.M. Kepp O. Tasdemir E. Maiuri M.C. Kroemer G. To die or not to die: that is the autophagic question.Curr. Mol. Med. 2008; 8: 78-91Crossref PubMed Scopus (211) Google Scholar]. While in a few experimental settings autophagy may contribute to cell death [7Kroemer G. Galluzzi L. Brenner C. Mitochondrial membrane permeabilization in cell death.Physiol. Rev. 2007; 87: 99-163Crossref PubMed Scopus (2639) Google Scholar, 8Kroemer G. Galluzzi L. Vandenabeele P. Abrams J. Alnemri E.S. Baehrecke E.H. Blagosklonny M.V. El-Deiry W.S. Golstein P. Green D.R. et al.Classification of cell death: recommendations of the Nomenclature Committee on Cell Death 2009.Cell Death Differ. 2009; 16: 3-11Crossref PubMed Scopus (2030) Google Scholar], in most circumstances autophagy constitutes a cytoprotective mechanism that is activated in response to a wide range of stressful conditions [9Kroemer G. Levine B. Autophagic cell death: the story of a misnomer.Nat. Rev. Mol. Cell Biol. 2008; 9: 1004-1010Crossref PubMed Scopus (1063) Google Scholar]. Moreover, baseline levels of autophagy have been shown to be required for the maintenance of intracellular homeostasis — for instance, by preventing the accumulation of aggregate-prone proteins or uncoupled (and hence potentially dangerous) mitochondria — and to exert oncosuppressive functions [10Morselli E. Galluzzi L. Kepp O. Vicencio J.M. Criollo A. Maiuri M.C. Kroemer G. Anti- and pro-tumor functions of autophagy.Biochim. Biophys. Acta. 2009; 1793: 1524-1532Crossref PubMed Scopus (289) Google Scholar]. Thus, the autophagic pathway has been implicated in human disorders as different as neurodegeneration, cancer, aging and infectious diseases [2Levine B. Kroemer G. Autophagy in the pathogenesis of disease.Cell. 2008; 132: 27-42Abstract Full Text Full Text PDF PubMed Scopus (4973) Google Scholar]. In particular, autophagy has emerged as a critical mechanism of host defense against viral, bacterial and parasitic infections (in this context, it has been dubbed ‘xenophagy’), and defective autophagy has been linked to increased susceptibility to infectious diseases, both in vitro and in vivo [11Virgin H.W. Levine B. Autophagy genes in immunity.Nat. Immunol. 2009; 10: 461-470Crossref PubMed Scopus (338) Google Scholar]. During the initial phase of autophagy, an isolation membrane that presumably derives from the endoplasmic reticulum begins to surround the cytosolic material to be degraded. This process can occur in a relatively non-specific fashion, for instance when the autophagic pathway is triggered by nutrient deprivation (and hence is aimed at generating novel substrates to meet the cell's energetic/anabolic demands), or it can be highly specific, for instance in response to pathogen invasion [12Mizushima N. Levine B. Cuervo A.M. Klionsky D.J. Autophagy fights disease through cellular self-digestion.Nature. 2008; 451: 1069-1075Crossref PubMed Scopus (4649) Google Scholar]. Multiple AuTophaGy-related (ATG) proteins, including the well-known ATG6/Beclin-1 and ATG8/LC3, are required for the correct execution of the autophagic program [12Mizushima N. Levine B. Cuervo A.M. Klionsky D.J. Autophagy fights disease through cellular self-digestion.Nature. 2008; 451: 1069-1075Crossref PubMed Scopus (4649) Google Scholar]. ATG16L1 also represents an essential autophagy modulator, as demonstrated by the fact that ATG16L1-deficient mice die in the first day of life (similar to atg5−/− and atg7−/− animals), presumably due to their inability to adapt to early postnatal starvation by activating autophagy [13Saitoh T. Fujita N. Jang M.H. Uematsu S. Yang B.G. Satoh T. Omori H. Noda T. Yamamoto N. Komatsu M. et al.Loss of the autophagy protein Atg16L1 enhances endotoxin-induced IL-1beta production.Nature. 2008; 456: 264-268Crossref PubMed Scopus (1460) Google Scholar]. ATG16L1-deficient cells are characterized by ineffective recruitment of the ATG5–ATG12 complex to the isolation membrane, and hence by an overall impairment of the autophagic machinery [13Saitoh T. Fujita N. Jang M.H. Uematsu S. Yang B.G. Satoh T. Omori H. Noda T. Yamamoto N. Komatsu M. et al.Loss of the autophagy protein Atg16L1 enhances endotoxin-induced IL-1beta production.Nature. 2008; 456: 264-268Crossref PubMed Scopus (1460) Google Scholar]. The Crohn's disease-associated atg16l1 risk allele encodes a protein with a threonine-to-alanine substitution (T300A) in its carboxy-terminal domain, which contains tryptophan-aspartate (WD) repeats [4Kuballa P. Huett A. Rioux J.D. Daly M.J. Xavier R.J. Impaired autophagy of an intracellular pathogen induced by a Crohn's disease associated ATG16L1 variant.PLoS ONE. 2008; 3: e3391Crossref PubMed Scopus (269) Google Scholar]. Although this domain of ATG16L1 is not conserved and is actually dispensable for the ATG16L1-dependent recruitment of ATG5–ATG12 complexes, as well as for starvation-induced autophagy, the ATG16L1 T300A mutant may exhibit a reduced stability and therefore fail to localize the autophagic machinery to invading bacteria [4Kuballa P. Huett A. Rioux J.D. Daly M.J. Xavier R.J. Impaired autophagy of an intracellular pathogen induced by a Crohn's disease associated ATG16L1 variant.PLoS ONE. 2008; 3: e3391Crossref PubMed Scopus (269) Google Scholar]. This hypothesis is supported by the observation that ATG16L1-hypomorphic mice (generated by the intronic insertion of a gene-trap vector within atg16l1) normally develop into adulthood, yet progressively accumulate histological abnormalities in the bowel that closely resemble changes in the ileum from those patients with Crohn's disease who are homozygous for the allele encoding the T300A ATG16L1 mutant [14Cadwell K. Liu J.Y. Brown S.L. Miyoshi H. Loh J. Lennerz J.K. Kishi C. Kc W. Carrero J.A. Hunt S. et al.A key role for autophagy and the autophagy gene Atg16l1 in mouse and human intestinal Paneth cells.Nature. 2008; 456: 259-263Crossref PubMed Scopus (1071) Google Scholar]. Notably, in both settings, Paneth cells, which normally provide a barrier to bacterial invasion by secreting antimicrobial products, exhibit morphological and ultrastructural alterations, and, in ATG16L1-hypomorphic animals, these cells lose the capacity to secrete the antimicrobial peptide lysozyme into the intestinal lumen [14Cadwell K. Liu J.Y. Brown S.L. Miyoshi H. Loh J. Lennerz J.K. Kishi C. Kc W. Carrero J.A. Hunt S. et al.A key role for autophagy and the autophagy gene Atg16l1 in mouse and human intestinal Paneth cells.Nature. 2008; 456: 259-263Crossref PubMed Scopus (1071) Google Scholar]. This suggests that defects in the molecular machinery for autophagy may contribute to Crohn's disease by affecting distinct cell types of the bowel, including local macrophages and Paneth cells. In macrophages, the absence of ATG16L1 has been associated with enhanced cytokine production in response to ligation of Toll-like receptors (TLRs) [13Saitoh T. Fujita N. Jang M.H. Uematsu S. Yang B.G. Satoh T. Omori H. Noda T. Yamamoto N. Komatsu M. et al.Loss of the autophagy protein Atg16L1 enhances endotoxin-induced IL-1beta production.Nature. 2008; 456: 264-268Crossref PubMed Scopus (1460) Google Scholar], which are known to act as PRRs and therefore play a prominent role in innate immunity. PRRs, which include (but are not limited to) NODs and TLRs, are characterized by the ability to recognize invading pathogens as well as other ‘danger signals’ and directly activate specific signal transduction pathways that alert host defenses [15Carneiro L.A. Magalhaes J.G. Tattoli I. Philpott D.J. Travassos L.H. Nod-like proteins in inflammation and disease.J. Pathol. 2008; 214: 136-148Crossref PubMed Scopus (141) Google Scholar]. Such biochemical cascades may vary depending on both cell-extrinsic and cell-intrinsic variables, including cell type and initiating stimulus. Thus, in non-myeloid cells infected by Shigella flexneri, NOD1 can activate the pro-inflammatory transcription factor NF-κB (via the receptor-interacting kinase RIP2) or can elicit a regulated form of necrosis (necroptosis, which also has inflammatory outcomes) [16Galluzzi L. Kroemer G. Shigella targets the mitochondrial checkpoint of programmed necrosis.Cell Host Microbe. 2009; 5: 107-109Abstract Full Text Full Text PDF PubMed Scopus (21) Google Scholar]. Similarly, NOD2 has been shown to respond to bacterial products by triggering a RIP2-dependent signal transduction cascade that eventually results in NF-κB activation [17Hasegawa M. Fujimoto Y. Lucas P.C. Nakano H. Fukase K. Nunez G. Inohara N. A critical role of RICK/RIP2 polyubiquitination in Nod-induced NF-kappaB activation.EMBO J. 2008; 27: 373-383Crossref PubMed Scopus (357) Google Scholar]. Consistent with the critical role of NODs in innate immunity, both nod1−/− and nod2−/− mice exhibit an increased susceptibility to infection by intracellular bacteria [18Viala J. Chaput C. Boneca I.G. Cardona A. Girardin S.E. Moran A.P. Athman R. Memet S. Huerre M.R. Coyle A.J. et al.Nod1 responds to peptidoglycan delivered by the Helicobacter pylori cag pathogenicity island.Nat. Immunol. 2004; 5: 1166-1174Crossref PubMed Scopus (937) Google Scholar, 19Kobayashi K.S. Chamaillard M. Ogura Y. Henegariu O. Inohara N. Nunez G. Flavell R.A. Nod2-dependent regulation of innate and adaptive immunity in the intestinal tract.Science. 2005; 307: 731-734Crossref PubMed Scopus (1417) Google Scholar]. The most prevalent nod2 polymorphism in Crohn's disease is L1007insC, resulting in a truncated NOD2 protein (NOD2FS) that fails to activate NF-κB in response to peptidoglycan [20Girardin S.E. Boneca I.G. Viala J. Chamaillard M. Labigne A. Thomas G. Philpott D.J. Sansonetti P.J. Nod2 is a general sensor of peptidoglycan through muramyl dipeptide (MDP) detection.J. Biol. Chem. 2003; 278: 8869-8872Crossref PubMed Scopus (1794) Google Scholar]. Altogether, these observations suggested that both autophagy and innate immunity are involved in the pathogenesis of Crohn's disease, and strongly pointed to some kind of cooperation between these processes, yet the molecular nature of this crosstalk was elusive. This gap has now been filled by Travassos and colleagues [5Travassos 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. 2009; 11: 55-62Crossref PubMed Scopus (938) Google Scholar], who have demonstrated that peptidoglycan sensing is functionally connected to the initiation of autophagy thanks to the interaction between NODs and ATG16L1 (Figure 1). In a variety of experimental settings (including ‘classical’ human cancer cell lines, nod1−/− and nod2−/− mice, as well as immortalized cells derived from Crohn's disease patients), these authors have demonstrated that NOD1 and NOD2 are critical for the autophagic response to invasive bacteria because they recruit ATG16L1 to bacterial entry sites at the plasma membrane. The interaction between NODs and ATGL16L1 (and the consequent induction of autophagy) persisted in rip2−/− mouse embryonic fibroblasts challenged with S. flexneri, suggesting that NODs mediate autophagy independent of NF-κB [5Travassos 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. 2009; 11: 55-62Crossref PubMed Scopus (938) Google Scholar]. Most importantly, the authors found that the Crohn's disease-associated truncated variant of NOD2 (NOD2FS, which unlike its wild-type counterpart is localized exclusively to the cytoplasm) fails to recruit ATG16L1 to the plasma membrane upon infection with intracellular bacteria. Co-immunoprecipitation assays revealed that, similar to wild-type NOD2, NOD2FS retains the ability to bind ATG16L1. However, in NOD2FS-expressing cells, ATG16L1 failed to relocalize to the sites of bacterial invasion, suggesting that NOD2FS might suppress the autophagy-modulatory functions of ATG16L1 by retaining it in the cytoplasm and hence preventing it from localizing at the plasma membrane. Accordingly, macrophages derived from the bone marrow of mice homozygous for the murine NOD2 mutation corresponding to the human Crohn's disease-associated L1007insC mutation displayed a striking xenophagy defect in response to S. flexneri infection [5Travassos 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. 2009; 11: 55-62Crossref PubMed Scopus (938) Google Scholar]. Taken together, the results by Travassos et al. [5Travassos 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. 2009; 11: 55-62Crossref PubMed Scopus (938) Google Scholar] establish a mechanistic link between modulators of innate immunity (i.e., NODs) and the cellular machinery for autophagy (and ATG16L1 in particular), which cooperate in the control of bacterial invasion. Thus, the NOD2–ATG16L1 axis appears for the first time as a unique pathway, the deregulation of which plays a central role in the etiology of Crohn's disease, with obvious therapeutic implications. Future investigations will have to elucidate whether the products of other loci that have been associated with Crohn's disease also interact with the molecular machinery for xenophagy." @default.
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• W2024134629 title "Bacterial Invasion: Linking Autophagy and Innate Immunity" @default.
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