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Felipe X. Pimentel-muiños - One of the best experts on this subject based on the ideXlab platform.
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Unconventional autophagy mediated by the WD40 domain of ATG16L1 is derailed by the T300A Crohn disease risk polymorphism
Autophagy, 2016Co-Authors: Inmaculada Serramito-gómez, Emilio Boada-romero, Felipe X. Pimentel-muiñosAbstract:A coding polymorphism of the critical autophagic effector ATG16L1 (T300A) increases the risk of Crohn disease, but how this mutation influences the function of ATG16L1 has remained unclear. In a recent report, we showed that the A300 allele alters the ability of the C-terminal WD40 domain of ATG16L1 to interact with proteins containing a specific amino acid motif able to recognize this region. This defect impairs the capacity of the motif-containing transmembrane molecule TMEM59 to induce the unconventional autophagic labeling of the same single-membrane vesicles where this protein is located. Such alteration derails the intracellular trafficking of TMEM59 and the xenophagic response against bacterial infection. In contrast, canonical autophagy remains unaffected in the presence of ATG16L1T300A. These data argue that the T300A polymorphism impairs the unconventional autophagic activities carried out by the WD40 domain, a region of ATG16L1 whose function has remained poorly understood.
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The T300A Crohn's disease risk polymorphism impairs function of the WD40 domain of ATG16L1
Nature communications, 2016Co-Authors: Emilio Boada-romero, David L. Boone, Ramnik J. Xavier, Inmaculada Serramito-gómez, María P. Sacristán, Felipe X. Pimentel-muiñosAbstract:A coding polymorphism of human ATG16L1 (rs2241880; T300A) increases the risk of Crohn's disease and it has been shown to enhance susceptibility of ATG16L1 to caspase cleavage. Here we show that T300A also alters the ability of the C-terminal WD40-repeat domain of ATG16L1 to interact with an amino acid motif that recognizes this region. Such alteration impairs the unconventional autophagic activity of TMEM59, a transmembrane protein that contains the WD40 domain-binding motif, and disrupts its normal intracellular trafficking and its ability to engage ATG16L1 in response to bacterial infection. TMEM59-induced autophagy is blunted in cells expressing the fragments generated by caspase processing of the ATG16L1-T300A risk allele, whereas canonical autophagy remains unaffected. These results suggest that the T300A polymorphism alters the function of motif-containing molecules that engage ATG16L1 through the WD40 domain, either by influencing this interaction under non-stressful conditions or by inhibiting their downstream autophagic signalling after caspase-mediated cleavage.
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TMEM59 defines a novel ATG16L1‐binding motif that promotes local activation of LC3
The EMBO journal, 2013Co-Authors: Emilio Boada-romero, Michal Letek, Aarne Fleischer, Kathrin Pallauf, Cristina Ramón‐barros, Felipe X. Pimentel-muiñosAbstract:Selective autophagy underlies many of the important physiological roles that autophagy plays in multicellular organisms, but the mechanisms involved in cargo selection are poorly understood. Here we describe a molecular mechanism that can target conventional endosomes for autophagic degradation. We show that the human transmembrane protein TMEM59 contains a minimal 19-amino-acid peptide in its intracellular domain that promotes LC3 labelling and lysosomal targeting of its own endosomal compartment. Interestingly, this peptide defines a novel protein motif that mediates interaction with the WD-repeat domain of ATG16L1, thus providing a mechanistic basis for the activity. The motif is represented with the same ATG16L1-binding ability in other molecules, suggesting a more general relevance. We propose that this motif may play an important role in targeting specific membranous compartments for autophagic degradation, and therefore it may facilitate the search for adaptor proteins that promote selective autophagy by engaging ATG16L1. Endogenous TMEM59 interacts with ATG16L1 and mediates autophagy in response to Staphylococcus aureus infection.
Indira U. Mysorekar - One of the best experts on this subject based on the ideXlab platform.
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ATG16L1 deficiency in macrophages drives clearance of Uropathogenic E. coli in an IL-1β dependent manner
Mucosal immunology, 2015Co-Authors: Jane W. Symington, Caihong Wang, Joy Twentyman, N Owusu-boaitey, Reto A. Schwendener, G Núñez, Joel D. Schilling, Indira U. MysorekarAbstract:Urinary tract infections (UTIs) are frequent, commonly recurrent, and costly. Deficiency in a key autophagy protein, ATG16L1, protects mice from infection with the predominant bacterial cause of UTIs, Uropathogenic E. coli (UPEC). Here, we report that loss of ATG16L1 in macrophages accounts for this protective phenotype. Compared with wild-type macrophages, macrophages deficient in ATG16L1 exhibit increased uptake of UPEC and enhanced secretion of interleukin-1β (IL-1β). The increased IL-1β production is dependent upon activation of the NLRP3 inflammasome and caspase-1. IL-1β secretion was also enhanced during UPEC infection of ATG16L1-deficient mice in vivo, and inhibition of IL-1β signaling abrogates the ATG16L1-dependent protection from UTIs. Our results argue that ATG16L1 normally suppresses a host-protective IL-1β response to UPEC by macrophages.
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NOD2 is dispensable for ATG16L1 deficiency-mediated resistance to urinary tract infection
Autophagy, 2013Co-Authors: Caihong Wang, Theo S. Plantinga, Xuejun Yuan, Graziella R Mendonsa, Lambertus A. Kiemeney, Sita H. Vermeulen, Indira U. MysorekarAbstract:NOD2 (nucleotide-binding oligomerization domain containing 2) functions as a pathogen sensor and is involved in development of Crohn disease, a form of inflammatory bowel disease. NOD2 functions in concert with the autophagy protein ATG16L1, which is also implicated in Crohn disease. Recently, we identified a novel protective role of ATG16L1 deficiency in uropathogenic Escherichia coli-induced urinary tract infections (UTIs), which are common infectious diseases in humans. Given the known roles of NOD2 in recruiting ATG16L1 to the bacterial entry site, autophagy induction, and Crohn disease, we hypothesized that NOD2 may also play an important role in UTI pathogenesis. Instead, we found evidence that NOD2 is dispensable in the pathogenesis of UTIs in mice and humans. First, loss of Nod2 did not affect the clearance of bacteriuria and the recruitment of innate immune cells to the bladder. Second, we showed that, although nod2(-/-) mice display increased kidney abscesses in the upper urinary tract, there were no increased bacterial loads or persistence in this niche. Third, although a previous study indicates that loss of Nod2 reverses the protection from intestinal infection afforded by loss of ATG16L1 in mice, we found NOD2 deficiency did not reverse the ATG16L1-deficiency-induced protection from UTI. Finally, a population-based study of a cohort of 1819 patients did not reveal any association of NOD2 polymorphisms with UTI incidence. Together, our data indicated that NOD2 is dispensable for UTI pathogenesis in both mice and humans and does not contribute to ATG16L1-deficiency-induced resistance to UTI in mice.
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ATG16L1 and pathogenesis of urinary tract infections.
Autophagy, 2012Co-Authors: Caihong Wang, Jane W. Symington, Indira U. MysorekarAbstract:Autophagy is generally considered to be antipathogenic. The autophagy gene ATG16L1 has a commonly occurring mutation associated with Crohn disease (CD) and intestinal cell abnormalities. Mice hypomorphic for ATG16L1 (ATG16L1(HM)) recreate specific features of CD. Our recent study shows that the same ATG16L1(HM) mice that are susceptible to intestinal inflammatory disease are protected from urinary tract infections (UTI), a common and important human disease primarily caused by uropathogenic E. coli (UPEC). UPEC colonize the bladder and exhibit both luminal and intra-epithelial stages. The host responds by recruiting innate immune cells and shedding infected epithelial cells to clear infection. Despite these countermeasures, UPEC can persist within the bladder epithelium as membrane-enclosed quiescent intracellular reservoirs (QIRs) that can seed recurrent UTI. The mechanisms of persistence remain unknown. In this study, we show that ATG16L1 deficiency protects the host against acute UTI and UPEC latency. ATG16L1(HM) mice clear urinary bacterial loads more rapidly and thoroughly due to ATG16L1-deficient innate immune components. Furthermore, ATG16L1(HM) mice exhibit superficial urothelial cell-autonomous architectural aberrations that also result in significantly reduced QIR numbers. Our findings reveal a host-protective effect of ATG16L1 deficiency in vivo against a common pathogen.
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ATG16L1 deficiency confers protection from uropathogenic Escherichia coli infection in vivo
Proceedings of the National Academy of Sciences of the United States of America, 2012Co-Authors: Caihong Wang, Jane W. Symington, Ken Cadwell, Graziella R Mendonsa, Qunyuan Zhang, Herbert W. Virgin, Indira U. MysorekarAbstract:Urinary tract infection (UTI), a frequent and important disease in humans, is primarily caused by uropathogenic Escherichia coli (UPEC). UPEC forms acute cytoplasmic biofilms within superficial urothelial cells and can persist by establishing membrane-enclosed latent reservoirs to seed recurrent UTI. The host responds with an influx of innate immune cells and shedding of infected epithelial cells. The autophagy gene ATG16L1 has a commonly occurring mutation that is associated with inflammatory disease and intestinal cell abnormalities in mice and humans. Here, we show that ATG16L1-deficient mice (ATG16L1HM) cleared bacteriuria more rapidly and thoroughly than controls and showed rapid epithelial recovery. ATG16L1 deficiency was associated with a potent proinflammatory cytokine response with increased recruitment of monocytes and neutrophils to infected bladders. Chimeric and genetic studies showed that ATG16L1HM hematopoietic cells alone could increase clearance and that ATG16L1-deficient innate immune cells were required and sufficient for enhanced bacteriuric clearance. We also show that ATG16L1-deficient mice exhibit cell-autonomous architectural aberrations of superficial urothelial cells, including increases in multivesicular bodies, lysosomes, and expression of the UPEC receptor Up1a. Finally, we show that ATG16L1HM epithelial cells contained a significantly reduced number of latent reservoirs. Together, our results show that ATG16L1 deficiency confers protection in vivo to the host against both acute and latent UPEC infection, suggest that deficiency in a key autophagy protein can be protective against infection in an animal model of one of the most common diseases of women worldwide, and may have significant clinical implications for understanding the etiology of recurrent UTIs.
Masatoshi Kudo - One of the best experts on this subject based on the ideXlab platform.
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ATG16L1 negatively regulates rick rip2 mediated innate immune responses
International Immunology, 2021Co-Authors: Hajime Honjo, Tomohiro Watanabe, Yasuyuki Arai, Ken Kamata, Kosuke Minaga, Yoriaki Komeda, Kouhei Yamashita, Masatoshi KudoAbstract:Polymorphisms in the autophagy-related protein 16 like 1 (ATG16L1) and nucleotide-binding oligomerization domain 2 (NOD2) genes are associated with Crohn's disease (CD). Impaired interaction between ATG16L1 and NOD2 underlies CD immunopathogenesis. Although activation of the receptor-interacting serine/threonine kinase (RICK, also known as RIP2), a downstream signaling molecule for NOD2 and multiple toll-like receptors (TLRs), plays a pathogenic role in the development of inflammatory bowel disease, the molecular interaction between ATG16L1 and RICK/RIP2 remains poorly understood. In this study, we examined the physical interaction between ATG16L1 and RICK/RIP2 in human embryonic kidney 293 (HEK293) cells and human monocyte-derived dendritic cells (DCs) expressing excessive and endogenous levels of these proteins, respectively. We established that ATG16L1 binds to RICK/RIP2 kinase domain and negatively regulates TLR2-mediated nuclear factor-kappa B (NF-κB) activation and proinflammatory cytokine responses by inhibiting the interaction between TLR2 and RICK/RIP2. Binding of ATG16L1 to RICK/RIP2 suppressed NF-κB activation by downregulating RICK/RIP2 polyubiquitination. Notably, the percentage of colonic DCs expressing ATG16L1 inversely correlated with IL-6 and TNF-α expression levels in the colon of CD patients. These data suggest that the interaction between ATG16L1 and RICK/RIP2 maintains intestinal homeostasis via the downregulation of TLR-mediated proinflammatory cytokine responses.
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ATG16L1 negatively regulates RICK/RIP2-mediated innate immune responses.
International immunology, 2020Co-Authors: Hajime Honjo, Tomohiro Watanabe, Yasuyuki Arai, Ken Kamata, Kosuke Minaga, Yoriaki Komeda, Kouhei Yamashita, Masatoshi KudoAbstract:Polymorphisms in the autophagy-related protein 16 like 1 (ATG16L1) and nucleotide-binding oligomerization domain 2 (NOD2) genes are associated with Crohn's disease (CD). Impaired interaction between ATG16L1 and NOD2 underlies CD immunopathogenesis. Although activation of the receptor-interacting serine/threonine kinase (RICK, also known as RIP2), a downstream signaling molecule for NOD2 and multiple toll-like receptors (TLRs), plays a pathogenic role in the development of inflammatory bowel disease, the molecular interaction between ATG16L1 and RICK/RIP2 remains poorly understood. In this study, we examined the physical interaction between ATG16L1 and RICK/RIP2 in human embryonic kidney 293 (HEK293) cells and human monocyte-derived dendritic cells (DCs) expressing excessive and endogenous levels of these proteins, respectively. We established that ATG16L1 binds to RICK/RIP2 kinase domain and negatively regulates TLR2-mediated nuclear factor-kappa B (NF-κB) activation and proinflammatory cytokine responses by inhibiting the interaction between TLR2 and RICK/RIP2. Binding of ATG16L1 to RICK/RIP2 suppressed NF-κB activation by downregulating RICK/RIP2 polyubiquitination. Notably, the percentage of colonic DCs expressing ATG16L1 inversely correlated with IL-6 and TNF-α expression levels in the colon of CD patients. These data suggest that the interaction between ATG16L1 and RICK/RIP2 maintains intestinal homeostasis via the downregulation of TLR-mediated proinflammatory cytokine responses.
David L. Boone - One of the best experts on this subject based on the ideXlab platform.
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The T300A Crohn's disease risk polymorphism impairs function of the WD40 domain of ATG16L1
Nature communications, 2016Co-Authors: Emilio Boada-romero, David L. Boone, Ramnik J. Xavier, Inmaculada Serramito-gómez, María P. Sacristán, Felipe X. Pimentel-muiñosAbstract:A coding polymorphism of human ATG16L1 (rs2241880; T300A) increases the risk of Crohn's disease and it has been shown to enhance susceptibility of ATG16L1 to caspase cleavage. Here we show that T300A also alters the ability of the C-terminal WD40-repeat domain of ATG16L1 to interact with an amino acid motif that recognizes this region. Such alteration impairs the unconventional autophagic activity of TMEM59, a transmembrane protein that contains the WD40 domain-binding motif, and disrupts its normal intracellular trafficking and its ability to engage ATG16L1 in response to bacterial infection. TMEM59-induced autophagy is blunted in cells expressing the fragments generated by caspase processing of the ATG16L1-T300A risk allele, whereas canonical autophagy remains unaffected. These results suggest that the T300A polymorphism alters the function of motif-containing molecules that engage ATG16L1 through the WD40 domain, either by influencing this interaction under non-stressful conditions or by inhibiting their downstream autophagic signalling after caspase-mediated cleavage.
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Human autophagy gene ATG16L1 is post-transcriptionally regulated by MIR142-3p.
Autophagy, 2014Co-Authors: Zili Zhai, Jeannette S. Messer, David L. Boone, Fengshi Dong, Alice Y. Chuang, John H. KwonAbstract:Multiple genetic studies have implicated the autophagy-related gene, ATG16L1, in the pathogenesis of Crohn disease (CD). While CD-related research on ATG16L1 has focused on the functional significance of ATG16L1 genetic variations, the mechanisms underlying the regulation of ATG16L1 expression are unclear. Our laboratory has described that microRNAs (miRNAs), key regulators of gene expression, are dysregulated in CD. Here, we report miRNA-mediated regulation of ATG16L1 in colonic epithelial cells as well as Jurkat T cells. Dual luciferase reporter assays following the transfection of vectors containing the ATG16L1 3′-untranslated region (3′UTR) or truncated 3′UTR fragments suggest that the first half of ATG16L1 3′UTR in the 5′ end is more functional for miRNA targeting. Of 5 tested miRNAs with putative binding sites within the region, MIR142-3p, upon transient overexpression in the cells, resulted in decreased ATG16L1 mRNA and protein levels. Further observation demonstrated that the luciferase reporter vector with a mutant MIR142-3p binding sequence in the 3′UTR was unresponsive to the inhibitory effect of MIR142-3p, suggesting ATG16L1 is a gene target of MIR142-3p. Moreover, the regulation of ATG16L1 expression by a MIR142-3p mimic blunted starvation- and L18-MDP-induced autophagic activity in HCT116 cells. Additionally, we found that a MIR142-3p inhibitor enhanced starvation-induced autophagy in Jurkat T cells. Our study reveals MIR142-3p as a new autophagy-regulating small molecule by targeting ATG16L1, implying a role of this miRNA in intestinal inflammation and CD.
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The Crohn's disease: associated ATG16L1 variant and Salmonella invasion.
BMJ open, 2013Co-Authors: Jeannette S. Messer, Stephen F. Murphy, Mark F Logsdon, James P. Lodolce, Wesley A Grimm, Sarah Bartulis, Tiphanie P. Vogel, Melisa Burn, David L. BooneAbstract:Objective A common genetic coding variant in the core autophagy gene ATG16L1 is associated with increased susceptibility to Crohn9s disease (CD). The variant encodes an amino acid change in ATG16L1 such that the threonine at position 300 is substituted with an alanine (ATG16L1 T300A). How this variant contributes to increased risk of CD is not known, but studies with transfected cell lines and gene-targeted mice have demonstrated that ATG16L1 is required for autophagy, control of interleukin-1-β and autophagic clearance of intracellular microbes. In addition, studies with human cells expressing ATG16L1 T300A indicate that this variant reduces the autophagic clearance of intracellular microbes. Design/Results We demonstrate, using somatically gene-targeted human cells that the ATG16L1 T300A variant confers protection from cellular invasion by Salmonella. In addition, we show that ATG16L1-deficient cells are resistant to bacterial invasion. Conclusions These results suggest that cellular expression of ATG16L1 facilitates bacterial invasion and that the CD-associated ATG16L1 T300A variant may confer protection from bacterial infection.
Emilio Boada-romero - One of the best experts on this subject based on the ideXlab platform.
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Unconventional autophagy mediated by the WD40 domain of ATG16L1 is derailed by the T300A Crohn disease risk polymorphism
Autophagy, 2016Co-Authors: Inmaculada Serramito-gómez, Emilio Boada-romero, Felipe X. Pimentel-muiñosAbstract:A coding polymorphism of the critical autophagic effector ATG16L1 (T300A) increases the risk of Crohn disease, but how this mutation influences the function of ATG16L1 has remained unclear. In a recent report, we showed that the A300 allele alters the ability of the C-terminal WD40 domain of ATG16L1 to interact with proteins containing a specific amino acid motif able to recognize this region. This defect impairs the capacity of the motif-containing transmembrane molecule TMEM59 to induce the unconventional autophagic labeling of the same single-membrane vesicles where this protein is located. Such alteration derails the intracellular trafficking of TMEM59 and the xenophagic response against bacterial infection. In contrast, canonical autophagy remains unaffected in the presence of ATG16L1T300A. These data argue that the T300A polymorphism impairs the unconventional autophagic activities carried out by the WD40 domain, a region of ATG16L1 whose function has remained poorly understood.
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The T300A Crohn's disease risk polymorphism impairs function of the WD40 domain of ATG16L1
Nature communications, 2016Co-Authors: Emilio Boada-romero, David L. Boone, Ramnik J. Xavier, Inmaculada Serramito-gómez, María P. Sacristán, Felipe X. Pimentel-muiñosAbstract:A coding polymorphism of human ATG16L1 (rs2241880; T300A) increases the risk of Crohn's disease and it has been shown to enhance susceptibility of ATG16L1 to caspase cleavage. Here we show that T300A also alters the ability of the C-terminal WD40-repeat domain of ATG16L1 to interact with an amino acid motif that recognizes this region. Such alteration impairs the unconventional autophagic activity of TMEM59, a transmembrane protein that contains the WD40 domain-binding motif, and disrupts its normal intracellular trafficking and its ability to engage ATG16L1 in response to bacterial infection. TMEM59-induced autophagy is blunted in cells expressing the fragments generated by caspase processing of the ATG16L1-T300A risk allele, whereas canonical autophagy remains unaffected. These results suggest that the T300A polymorphism alters the function of motif-containing molecules that engage ATG16L1 through the WD40 domain, either by influencing this interaction under non-stressful conditions or by inhibiting their downstream autophagic signalling after caspase-mediated cleavage.
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TMEM59 defines a novel ATG16L1‐binding motif that promotes local activation of LC3
The EMBO journal, 2013Co-Authors: Emilio Boada-romero, Michal Letek, Aarne Fleischer, Kathrin Pallauf, Cristina Ramón‐barros, Felipe X. Pimentel-muiñosAbstract:Selective autophagy underlies many of the important physiological roles that autophagy plays in multicellular organisms, but the mechanisms involved in cargo selection are poorly understood. Here we describe a molecular mechanism that can target conventional endosomes for autophagic degradation. We show that the human transmembrane protein TMEM59 contains a minimal 19-amino-acid peptide in its intracellular domain that promotes LC3 labelling and lysosomal targeting of its own endosomal compartment. Interestingly, this peptide defines a novel protein motif that mediates interaction with the WD-repeat domain of ATG16L1, thus providing a mechanistic basis for the activity. The motif is represented with the same ATG16L1-binding ability in other molecules, suggesting a more general relevance. We propose that this motif may play an important role in targeting specific membranous compartments for autophagic degradation, and therefore it may facilitate the search for adaptor proteins that promote selective autophagy by engaging ATG16L1. Endogenous TMEM59 interacts with ATG16L1 and mediates autophagy in response to Staphylococcus aureus infection.