* 610767

AUTOPHAGY 16-LIKE 1; ATG16L1


Alternative titles; symbols

APG16-LIKE; APG16L


HGNC Approved Gene Symbol: ATG16L1

Cytogenetic location: 2q37.1     Genomic coordinates (GRCh38): 2:233,251,673-233,295,669 (from NCBI)


Gene-Phenotype Relationships
Location Phenotype Phenotype
MIM number
Inheritance Phenotype
mapping key
2q37.1 {Inflammatory bowel disease (Crohn disease) 10} 611081 3

TEXT

Description

Autophagy is the major intracellular degradation system delivering cytoplasmic components to lysosomes, and it accounts for degradation of most long-lived proteins and some organelles. Cytoplasmic constituents, including organelles, are sequestered into double-membraned autophagosomes, which subsequently fuse with lysosomes. ATG16L1 is a component of a large protein complex essential for autophagy (Mizushima et al., 2003).


Cloning and Expression

Mizushima et al. (2003) cloned mouse Atg16l1, which encodes a deduced 623-amino acid protein with an N-terminal coiled-coil region and 7 WD repeats. They also identified 2 Atg16l1 isoforms with different sequences between the coiled-coil region and WD repeats. The N-terminal region of Atg16l1 shares weak but significant homology with S. cerevisiae Apg16, but the C-terminal region is absent from the S. cerevisiae protein. By database analysis, Mizushima et al. (2003) identified a human ATG16L1 transcript encoding a deduced 588-amino acid protein that corresponds to the shortest mouse isoform. Western blot analysis of mouse tissues detected a major 63-kD Atg16l1 protein and a minor 71-kD protein in liver, kidney, spleen, thymus, testis, and embryonic stem cells, and a 75-kD protein in brain, skeletal muscle, and heart.

By large-scale sequence analysis of a human fetal brain cDNA library, Zheng et al. (2004) obtained a full-length ATG16L1 cDNA. The deduced 607-amino acid protein has a calculated molecular mass of 68.2 kD and shares 90% identity with one of the mouse Atg16l1 isoforms. By database analysis, Zheng et al. (2004) identified 3 ATG16L1 splice variants that encode proteins of 470, 504, and 523 amino acids. All 4 ATG16L1 isoforms have an N-terminal coiled-coil domain, and the 3 longest isoforms have 7 C-terminal WD repeats. The shortest isoform has only 3 C-terminal WD repeats.


Gene Structure

Zheng et al. (2004) determined that the ATG16L1 gene contains 19 exons and spans more than 43.9 kD.


Mapping

By genomic sequence analysis, Zheng et al. (2004) mapped the ATG16L1 gene to chromosome 2q37.1.


Gene Function

Using coimmunoprecipitation analysis, Mizushima et al. (2003) found that mouse Atg16l1 interacted with Apg5 (ATG5; 604261), but not with Apg12 (ATG12; 609608), and that Atg16l1 could form homodimers. These interactions did not require the WD repeat domain of Atg16l1. In conjunction with Apg12-Apg5 dimers, Atg16l1 associated with the autophagic isolation membrane for the duration of autophagosome formation. Membrane targeting of Atg16l1 required Apg5, but not Apg12. Mizushima et al. (2003) concluded that Atg16l1 is the functional counterpart of yeast Apg16.

Cooney et al. (2010) showed that activation of NOD2 (605956) with muramyldipeptide induced autophagy in dendritic cells (DCs) that required RIPK2 (603455), PI3K (see 601232), ATG5, ATG7 (608760), and ATG16L1, but not NALP3 (NLRP3; 606416). DCs from Crohn disease (CD; 266600) patients with susceptibility variants in NOD2 (e.g., 1007fs; 605956.0001) or ATG16L1 (T300A; 610767.0001) were deficient in autophagy induction. DCs from CD patients with NOD2 variants also showed reduced localization of bacteria in autophagolysosomes, which could be reversed by treatment with rapamycin. Cooney et al. (2010) concluded that NOD2 influences bacterial degradation and interacts with the major histocompatibility complex class II antigen presentation machinery within DCs, and that ATG16L1 and NOD2 are linked within 1 functional pathway.

Adolph et al. (2013) showed that impairment of either the unfolded protein response (UPR) or autophagy function in intestinal epithelial cells results in each other's compensatory engagement, and severe spontaneous Crohn disease (see 266600)-like transmural ileitis if both mechanisms are compromised. Xbp1 (194355)-deficient mouse intestinal epithelial cells showed autophagosome formation in hypomorphic Paneth cells, which is linked to endoplasmic reticulum (ER) stress via protein kinase RNA-like ER kinase (PERK; 604032), elongation initiation factor 2-alpha (eIF2-alpha; 609234), and activating transcription factor-4 (ATF4; 604064). Ileitis is dependent on commensal microbiota and derives from increased intestinal epithelial cell death, inositol-requiring enzyme 1-alpha (IRE1-alpha; 604033)-regulated NF-kappa-B (see 164011) activation, and tumor necrosis factor (TNF; 191160) signaling, which are synergistically increased when autophagy is deficient. ATG16L1 restrains IRE1-alpha activity, and augmentation of autophagy in intestinal epithelial cells ameliorates ER stress-induced intestinal inflammation and eases NF-kappa-B overactivation and intestinal epithelial cell death. ER stress, autophagy induction, and spontaneous ileitis emerge from Paneth cell-specific deletion of Xbp1. Adolph et al. (2013) concluded that genetically and environmentally controlled UPR function within Paneth cells may therefore set the threshold for the development of intestinal inflammation upon hypomorphic ATG16L1 function and implicate ileal Crohn disease as a specific disorder of Paneth cells.

The human commensal Bacteroides fragilis delivers immunomodulatory molecules to immune cells via secretion of outer membrane vesicles (OMVs). Chu et al. (2016) found that OMVs require the inflammatory bowel disease (IBD; see 266600)-associated genes ATG16L1 and NOD2 to activate a noncanonical autophagy pathway during protection from colitis. ATG16L1-deficient dendritic cells do not induce regulatory T cells (T(regs)) to suppress mucosal inflammation. Immune cells from human subjects with a major risk variant in ATG16L1 are defective in T(reg) responses to OMVs. Chu et al. (2016) proposed that polymorphisms in susceptibility genes promote disease through defects in 'sensing' protective signals from the microbiome, defining a potentially critical gene-environment etiology for IBD.

In mice, Bel et al. (2017) showed that during bacterial infection with the Salmonella enterica serovar Typhimurium, lysozyme is rerouted via secretory autophagy, an autophagy-based alternative secretion pathway. Secretory autophagy was triggered in Paneth cells by bacteria-induced ER stress, requiring extrinsic signals from innate lymphoid cells, and limited bacterial dissemination. Secretory autophagy was disrupted in Paneth cells of mice harboring a mutation in the autophagy gene Atg16L1 that confers increased risk for Crohn disease in humans. Bel et al. (2017) concluded that their findings identified a role for secretory autophagy in intestinal defense and helped elucidate why Crohn disease is associated with genetic mutations that affect both the ER stress response and autophagy.

Keller et al. (2020) demonstrated that ATG16L1 and other ATG proteins mediate protection against alpha-toxin through the release of ADAM10 (602192) on exosomes (extracellular vesicles of endosomal origin). Bacterial DNA and CpG DNA induced the secretion of ADAM10-bearing exosomes from human cells as well as in mice. Transferred exosomes protected host cells in vitro by serving as scavengers that could bind multiple toxins, and improved the survival of mice infected with MRSA in vivo. Keller et al. (2020) concluded that their findings indicated that ATG proteins mediate a previously unknown form of defense in response to infection, facilitating the release of exosomes that serve as decoys for bacterially produced toxins.


Molecular Genetics

In a genomewide association study of 19,779 nonsynonymous SNPs in 735 individuals with Crohn disease (see IBD10, 611081) and 368 controls, Hampe et al. (2007) identified an A-to-G transition in the ATG16L1 gene (T300A; 610767.0001; rs2241880) that was associated with Crohn disease (CD). The association was replicated in independent CD populations by Rioux et al. (2007) and Franke et al. (2008). In studies in human epithelial cells, Kuballa et al. (2008) demonstrated that the ala300-containing variant had markedly decreased efficiency of Salmonella autophagy compared to the wildtype thr300-containing variant, and suggested that the association of rs2241880 with increased risk of CD is due to impaired bacterial handling and lowered rates of bacterial capture by autophagy.


Animal Model

Cadwell et al. (2008) generated and characterized mice that were hypomorphic for Atg16l1 protein expression and validated conclusions on the basis of studies in mice by analyzing intestinal tissues that they collected from Crohn disease patients carrying the Crohn disease risk allele of ATG16L1. Cadwell et al. (2008) showed that ATG16L1 is a bona fide autophagy protein. Within the ileal epithelium, both ATG16L1 and a second essential autophagy protein, ATG5, are selectively important for the biology of the Paneth cell, a specialized epithelial cell that functions in part by secretion of granule contents containing antimicrobial peptides and other proteins that alter the intestinal environment. Atg16L1- and Atg5-deficient Paneth cells exhibited notable abnormalities in the granule exocytosis pathway. In addition, transcriptional analysis revealed an unexpected gain of function specific to Atg16L1-deficient Paneth cells including increased expression of genes involved in peroxisome proliferator-activated receptor (PPAR) signaling and lipid metabolism, of acute phase reactants and of 2 adipocytokines, leptin (164160) and adiponectin (605441), known to directly influence intestinal injury responses. Importantly, Crohn disease patients homozygous for the ATG16L1 Crohn disease risk allele displayed Paneth cell granule abnormalities similar to those observed in autophagy protein-deficient mice and expressed increased levels of leptin protein. Thus, Cadwell et al. (2008) concluded that ATG16L1, and probably the process of autophagy, have a role within the intestinal epithelium of mice and Crohn disease patients by selective effects on the cell biology and specialized regulatory properties of Paneth cells.

Saitoh et al. (2008) showed that Atg16L1 regulates endotoxin-induced inflammasome activation in mice. Atg16L1 deficiency disrupts the recruitment of the Atg12-Atg5 conjugate to the isolation membrane, resulting in a loss of microtubule-associated protein 1 light chain 3 (LC3; 601242) conjugation to phosphatidylethanolamine. Consequently, both autophagosome formation and degradation of long-lived proteins are severely impaired in Atg16L1-deficient cells. Following stimulation with lipopolysaccharide, a ligand for Toll-like receptor-4 (TLR4; 603030), Atg16L1-deficient macrophages produce high amounts of the inflammatory cytokines IL1-beta (147720) and IL18 (600953). In lipopolysaccharide-stimulated macrophages, Atg16L1 deficiency causes IFN-beta (TRIF; 607601)-dependent activation of caspase-1 (147678), leading to increased production of IL1-beta. Mice lacking Atg16L1 in hematopoietic cells are highly susceptible to dextran sulfate sodium-induced acute colitis, which is alleviated by injection of anti-IL1-beta and IL18 antibodies, indicating the importance of Atg16L1 in the suppression of intestinal inflammation. Saitoh et al. (2008) concluded that ATG16L1 is an essential component of the autophagic machinery responsible for control of the endotoxin-induced inflammatory immune response.

Cadwell et al. (2010) studied mice with hypomorphic Atgl1 protein expression and reduced autophagy that had been raised in an enhanced barrier facility. They detected abnormalities in Paneth cell morphology and granule packaging after infection of these mice with murine norovirus. Subsequently, the response to injury induced by dextran sodium sulfate altered the pathologic picture to resemble Crohn disease. The pathology induced by the virus-plus-susceptibility gene interaction was dependent on Tnf (191160) and Ifng (147570), and it could be prevented by treatment with broad spectrum antibiotics. Mice in the enhanced facility that were not exposed to the virus did not get disease. Cadwell et al. (2010) proposed that the model could explain how virus-plus-susceptibility gene interaction, in combination with environmental insults and commensal bacteria, determines a disease phenotype in hosts carrying common risk alleles for inflammatory disease.

Tschurtschenthaler et al. (2017) observed that mice lacking Atg16l1 in intestinal epithelial cells (IECs) spontaneously developed transmural ileitis phenocopying ileal CD in an age-dependent manner. The ileitis was driven by the ER stress sensor Ire1a, which accumulated in Paneth cells. Humans homozygous for ATG16L1 T300A also exhibited increased IRE1A in intestinal epithelial crypts. Whereas Ire1b (604034) could be protective, hyperactivated Ire1a led to a similar ileitis in younger mice lacking both Atg16l1 and Xbp1 in IECs. Optineurin (OPTN; 602432) interacted with Ire1a, and Optn deficiency amplified Ire1a levels during ER stress. Although there was dysbiosis of the ileal microbiota in mice lacking Atg16l1 and Xbp1 in IECs, accompanied by impaired Paneth cell antimicrobial function, such structural alteration of the microbiota did not trigger ileitis, but rather aggravated dextran sodium sulfate-induced colitis. Tschurtschenthaler et al. (2017) concluded that defective autophagy in IECs may predispose to CD ileitis via impaired clearance of IRE1A aggregates during ER stress.


ALLELIC VARIANTS ( 1 Selected Example):

.0001 INFLAMMATORY BOWEL DISEASE (CROHN DISEASE) 10, SUSCEPTIBILITY TO

ATG16L1, THR300ALA (rs2241880)
  
RCV000001189...

In a genomewide association study of 19,779 nonsynonymous SNPs in 735 individuals with Crohn disease (see IBD10, 611081) and 368 controls, Hampe et al. (2007) identified a nonsynonymous SNP (A-to-G; rs2241880) in the ATG16L1 gene, resulting in thr300-to-ala (T300A) substitution, that was associated with Crohn disease (CD). The association was replicated in independent populations by Rioux et al. (2007) and Franke et al. (2008). In studies in human epithelial cells, Kuballa et al. (2008) demonstrated that the ala300-containing variant had markedly decreased efficiency in capture of internalized Salmonella within autophagosomes compared to the wildtype thr300-containing variant, and suggested that the association of rs2241880 with increased risk of CD is due to impaired bacterial handling and lowered rates of bacterial capture by autophagy.

In a metaanalysis of 24 studies involving a total of 13,022 CD cases and 17,532 controls, Zhang et al. (2009) confirmed the association of rs2241880 with CD risk in Caucasians (p less than 0.01). No significant association was found in Asians. Zhang et al. (2009) suggested that the G allele is a low-penetrant allele for developing CD in Caucasians.

Murthy et al. (2014) showed that amino acids 296 to 299 of ATG16L1 constitute a caspase cleavage motif and that the T300A variant (T316A in mice) significantly increases ATG16L1 sensitization to CASP3 (600636)-mediated processing. Murthy et al. (2014) observed that death receptor activation or starvation-induced metabolic stress in human and murine macrophages increased degradation of the T300A or T316A variants of ATG16L1, respectively, resulting in diminished autophagy. Knockin mice harboring the T316A variant showed defective clearance of the ileal pathogen Yersinia enterocolitica and an elevated inflammatory cytokine response. In turn, deletion of Casp3 or elimination of the caspase cleavage site by site-directed mutagenesis rescued starvation-induced autophagy and pathogen clearance, respectively. Murthy et al. (2014) concluded that these findings demonstrated that CASP3 activation in the presence of a common risk allele leads to accelerated degradation of ATG16L1, placing cellular stress, apoptotic stimuli, and impaired autophagy in a unified pathway that predisposes to Crohn disease.

Boada-Romero et al. (2016) showed that the T300A polymorphism altered the ability of the ATG16L1 C-terminal WD40 repeat domain to interact with molecules containing a motif that recognizes this region, including TMEM59 (617084), T3JAM (TRAF3IP3; 608255), and DEDD2 (617078). The polymorphism impaired the unconventional autophagic activity of the transmembrane protein TMEM59 and disrupted its normal intracellular trafficking and its ability to engage ATG16L1 in response to S. aureus infection. TMEM59-induced autophagy was blunted in cells expressing fragments generated by caspase processing of ATG16L1 with T300A, whereas canonical autophagy remained unaffected. Boada-Romero et al. (2016) proposed that the T300A polymorphism alters the function of molecules that interact with ATG16L1 via the WD40 repeat domain-binding motif, either by influencing the interaction under nonstressful conditions or by inhibiting their downstream autophagic signaling after caspase-mediated cleavage.


REFERENCES

  1. 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., Flak, M. B., Cusick, J. L., and 14 others. Paneth cells as a site of origin for intestinal inflammation. Nature 503: 272-276, 2013. [PubMed: 24089213, images, related citations] [Full Text]

  2. Bel, S., Pendse, M., Wang, Y., Li, Y., Ruhn, K. A., Hassell, B., Leal, T., Winter, S. E., Xavier, R. J., Hooper, L. V. Paneth cells secrete lysozyme via secretory autophagy during bacterial infection of the intestine. Science 357: 1047-1052, 2017. [PubMed: 28751470, related citations] [Full Text]

  3. Boada-Romero, E., Serramito-Gomez, I., Sacristan, M. P., Boone, D. L., Xavier, R. J., Pimentel-Muinos, F. X. The T300A Crohn's disease risk polymorphism impairs function of the WD40 domain of ATG16L1. Nature Commun. 7: 11821, 2016. Note: Electronic Article. [PubMed: 27273576, images, related citations] [Full Text]

  4. Cadwell, K., Liu, J. Y., Brown, S. L., Miyoshi, H., Loh, J., Lennerz, J. K., Kishi, C., Kc, W., Carrero, J. A., Hunt, S., Stone, C. D., Brunt, E. M., Xavier, R. J., Sleckman, B. P., Li, E., Mizushima, N., Stappenbeck, T. S., Virgin, H. W., IV. A key role for autophagy and the autophagy gene Atg16l1 in mouse and human intestinal Paneth cells. Nature 456: 259-263, 2008. [PubMed: 18849966, images, related citations] [Full Text]

  5. Cadwell, K., Patel, K. K., Maloney, N. S., Liu, T.-C., Ng, A. C. Y., Storer, C. E., Head, R. D., Xavier, R., Stappenbeck, T. S., Virgin, H. W. Virus-plus-susceptibility gene interaction determines Crohn's disease gene Atg16L1 phenotypes in intestine. Cell 141: 1135-1145, 2010. [PubMed: 20602997, images, related citations] [Full Text]

  6. Chu, H., Khosravi, A., Kusumawardhani, I. P., Kwon, A. H. K., Vasconcelos, A. C., Cunha, L. D., Mayer, A. E., Shen, Y., Wu, W.-L., Kambal, A., Targan, S. R., Xavier, R. J., Ernst, P. B., Green, D. R., McGovern, D. P. B., Virgin, H. W., Mazmanian, S. K. Gene-microbiota interactions contribute to the pathogenesis of inflammatory bowel disease. Science 352: 1116-1120, 2016. [PubMed: 27230380, images, related citations] [Full Text]

  7. Cooney, R., Baker, J., Brain, O., Danis, B., Pichulik, T., Allan, P., Ferguson, D. J. P., Campbell, B. J., Jewell, D., Simmons, A. NOD2 stimulation induces autophagy in dendritic cells influencing bacterial handling and antigen presentation. Nature Med. 16: 90-97, 2010. [PubMed: 19966812, related citations] [Full Text]

  8. Franke, A., Balschun, T., Karlsen, T. H., Hedderich, J., May, S., Lu, T., Schuldt, D., Nikolaus, S., Rosenstiel, P., Krawczak, M., Schreiber, S. Replication of signals from recent studies of Crohn's disease identifies previously unknown disease loci for ulcerative colitis. Nature Genet. 40: 713-715, 2008. [PubMed: 18438405, related citations] [Full Text]

  9. Hampe, J., Franke, A., Rosenstiel, P., Till, A., Teuber, M., Huse, K., Albrecht, M., Mayr, G., De La Vega, F. M., Briggs, J., Gunther, S., Prescott, N. J., and 9 others. A genome-wide association scan of nonsynonymous SNPs identifies a susceptibility variant for Crohn disease in ATG16L1. Nature Genet. 39: 207-211, 2007. [PubMed: 17200669, related citations] [Full Text]

  10. Keller, M. D., Ching, K. L., Liang, F.-X., Dhabaria, A., Tam, K., Ueberheide, B. M., Unutmaz, D., Torres, V. J., Cadwell, K. Decoy exosomes provide protection against bacterial toxins. Nature 579: 260-264, 2020. [PubMed: 32132711, related citations] [Full Text]

  11. Kuballa, 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 3: e3391, 2008. Note: Electronic Article. [PubMed: 18852889, images, related citations] [Full Text]

  12. Mizushima, N., Kuma, A., Kobayashi, Y., Yamamoto, A., Matsubae, M., Takao, T., Natsume, T., Ohsumi, Y., Yoshimori, T. Mouse Apg16L, a novel WD-repeat protein, targets to the autophagic isolation membrane with the Apg12-Apg5 conjugate. J. Cell Sci. 116: 1679-1688, 2003. [PubMed: 12665549, related citations] [Full Text]

  13. Murthy, A., Li, Y., Peng, I., Reichelt, M., Katakam, A. K., Noubade, R., Roose-Girma, M., DeVoss, J., Diehl, L., Graham, R. R., van Lookeren Campagne, M. A Crohn's disease variant in Atg16l1 enhances its degradation by caspase 3. Nature 506: 456-462, 2014. [PubMed: 24553140, related citations] [Full Text]

  14. Rioux, J. D., Xavier, R. J., Taylor, K. D., Silverberg, M. S., Goyette, P., Huett, A., Green, T., Kuballa, P., Barmada, M. M., Datta, L. W., Shugart, Y. Y., Griffiths, A. M., and 13 others. Genome-wide association study identifies new susceptibility loci for Crohn disease and implicates autophagy in disease pathogenesis. Nature Genet. 39: 596-604, 2007. [PubMed: 17435756, images, related citations] [Full Text]

  15. Saitoh, T., Fujita, N., Jang, M. H., Uematsu, S., Yang, B.-G., Satoh, T., Omori, H., Noda, T., Yamamoto, N., Komatsu, M., Tanaka, K., Kawai, T., Tsujimura, T., Takeuchi, O., Yoshimori, T., Akira, S. Loss of the autophagy protein Atg16L1 enhances endotoxin-induced IL-1-beta production. Nature 456: 264-268, 2008. [PubMed: 18849965, related citations] [Full Text]

  16. 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., Parkes, M., Kohno, K., and 10 others. Defective ATG16L1-mediated removal of IRE1-alpha drives Crohn's disease-like ileitis. J. Exp. Med. 214: 401-422, 2017. [PubMed: 28082357, related citations] [Full Text]

  17. Zhang, H.-F., Qiu, L.-X., Chen, Y., Zhu, W.-L., Mao, C., Zhu, L.-G., Zheng, M.-H., Wang, Y., Lei, L., Shi, J. ATG16L1 T300A polymorphism and Crohn's disease susceptibility: evidence from 13,022 cases and 17,532 controls. Hum. Genet. 125: 627-631, 2009. [PubMed: 19337756, related citations] [Full Text]

  18. Zheng, H., Ji, C., Li, J., Jiang, H., Ren, M., Lu, Q., Gu, S., Mao, Y., Xie, Y. Cloning and analysis of human Apg16L. DNA Seq. 15: 303-305, 2004. [PubMed: 15620219, related citations] [Full Text]


Ada Hamosh - updated : 06/29/2020
Paul J. Converse - updated : 01/02/2018
Ada Hamosh - updated : 11/28/2017
Ada Hamosh - updated : 09/01/2016
Marla J. F. O'Neill - updated : 7/6/2016
Ada Hamosh - updated : 3/31/2014
Ada Hamosh - updated : 12/13/2013
Paul J. Converse - updated : 6/14/2011
Marla J. F. O'Neill - updated : 7/28/2010
Paul J. Converse - updated : 2/4/2010
Marla J. F. O'Neill - updated : 5/7/2009
Ada Hamosh - updated : 11/26/2008
Marla J. F. O'Neill - updated : 10/28/2008
Ada Hamosh - updated : 7/24/2007
Victor A. McKusick - updated : 5/31/2007
Victor A. McKusick - updated : 5/24/2007
Creation Date:
Patricia A. Hartz : 2/15/2007
alopez : 06/29/2020
mgross : 01/03/2018
mgross : 01/02/2018
alopez : 11/28/2017
alopez : 09/01/2016
alopez : 08/25/2016
alopez : 08/19/2016
carol : 08/01/2016
mgross : 07/06/2016
mgross : 7/6/2016
alopez : 3/31/2014
alopez : 12/13/2013
mgross : 6/20/2011
mgross : 6/20/2011
terry : 6/14/2011
wwang : 7/30/2010
terry : 7/28/2010
mgross : 2/15/2010
terry : 2/4/2010
wwang : 5/12/2009
wwang : 5/12/2009
terry : 5/7/2009
alopez : 12/10/2008
terry : 11/26/2008
carol : 10/28/2008
alopez : 8/28/2008
carol : 8/15/2008
alopez : 7/24/2007
alopez : 6/5/2007
terry : 5/31/2007
terry : 5/24/2007
mgross : 2/15/2007

* 610767

AUTOPHAGY 16-LIKE 1; ATG16L1


Alternative titles; symbols

APG16-LIKE; APG16L


HGNC Approved Gene Symbol: ATG16L1

Cytogenetic location: 2q37.1     Genomic coordinates (GRCh38): 2:233,251,673-233,295,669 (from NCBI)


Gene-Phenotype Relationships

Location Phenotype Phenotype
MIM number
Inheritance Phenotype
mapping key
2q37.1 {Inflammatory bowel disease (Crohn disease) 10} 611081 3

TEXT

Description

Autophagy is the major intracellular degradation system delivering cytoplasmic components to lysosomes, and it accounts for degradation of most long-lived proteins and some organelles. Cytoplasmic constituents, including organelles, are sequestered into double-membraned autophagosomes, which subsequently fuse with lysosomes. ATG16L1 is a component of a large protein complex essential for autophagy (Mizushima et al., 2003).


Cloning and Expression

Mizushima et al. (2003) cloned mouse Atg16l1, which encodes a deduced 623-amino acid protein with an N-terminal coiled-coil region and 7 WD repeats. They also identified 2 Atg16l1 isoforms with different sequences between the coiled-coil region and WD repeats. The N-terminal region of Atg16l1 shares weak but significant homology with S. cerevisiae Apg16, but the C-terminal region is absent from the S. cerevisiae protein. By database analysis, Mizushima et al. (2003) identified a human ATG16L1 transcript encoding a deduced 588-amino acid protein that corresponds to the shortest mouse isoform. Western blot analysis of mouse tissues detected a major 63-kD Atg16l1 protein and a minor 71-kD protein in liver, kidney, spleen, thymus, testis, and embryonic stem cells, and a 75-kD protein in brain, skeletal muscle, and heart.

By large-scale sequence analysis of a human fetal brain cDNA library, Zheng et al. (2004) obtained a full-length ATG16L1 cDNA. The deduced 607-amino acid protein has a calculated molecular mass of 68.2 kD and shares 90% identity with one of the mouse Atg16l1 isoforms. By database analysis, Zheng et al. (2004) identified 3 ATG16L1 splice variants that encode proteins of 470, 504, and 523 amino acids. All 4 ATG16L1 isoforms have an N-terminal coiled-coil domain, and the 3 longest isoforms have 7 C-terminal WD repeats. The shortest isoform has only 3 C-terminal WD repeats.


Gene Structure

Zheng et al. (2004) determined that the ATG16L1 gene contains 19 exons and spans more than 43.9 kD.


Mapping

By genomic sequence analysis, Zheng et al. (2004) mapped the ATG16L1 gene to chromosome 2q37.1.


Gene Function

Using coimmunoprecipitation analysis, Mizushima et al. (2003) found that mouse Atg16l1 interacted with Apg5 (ATG5; 604261), but not with Apg12 (ATG12; 609608), and that Atg16l1 could form homodimers. These interactions did not require the WD repeat domain of Atg16l1. In conjunction with Apg12-Apg5 dimers, Atg16l1 associated with the autophagic isolation membrane for the duration of autophagosome formation. Membrane targeting of Atg16l1 required Apg5, but not Apg12. Mizushima et al. (2003) concluded that Atg16l1 is the functional counterpart of yeast Apg16.

Cooney et al. (2010) showed that activation of NOD2 (605956) with muramyldipeptide induced autophagy in dendritic cells (DCs) that required RIPK2 (603455), PI3K (see 601232), ATG5, ATG7 (608760), and ATG16L1, but not NALP3 (NLRP3; 606416). DCs from Crohn disease (CD; 266600) patients with susceptibility variants in NOD2 (e.g., 1007fs; 605956.0001) or ATG16L1 (T300A; 610767.0001) were deficient in autophagy induction. DCs from CD patients with NOD2 variants also showed reduced localization of bacteria in autophagolysosomes, which could be reversed by treatment with rapamycin. Cooney et al. (2010) concluded that NOD2 influences bacterial degradation and interacts with the major histocompatibility complex class II antigen presentation machinery within DCs, and that ATG16L1 and NOD2 are linked within 1 functional pathway.

Adolph et al. (2013) showed that impairment of either the unfolded protein response (UPR) or autophagy function in intestinal epithelial cells results in each other's compensatory engagement, and severe spontaneous Crohn disease (see 266600)-like transmural ileitis if both mechanisms are compromised. Xbp1 (194355)-deficient mouse intestinal epithelial cells showed autophagosome formation in hypomorphic Paneth cells, which is linked to endoplasmic reticulum (ER) stress via protein kinase RNA-like ER kinase (PERK; 604032), elongation initiation factor 2-alpha (eIF2-alpha; 609234), and activating transcription factor-4 (ATF4; 604064). Ileitis is dependent on commensal microbiota and derives from increased intestinal epithelial cell death, inositol-requiring enzyme 1-alpha (IRE1-alpha; 604033)-regulated NF-kappa-B (see 164011) activation, and tumor necrosis factor (TNF; 191160) signaling, which are synergistically increased when autophagy is deficient. ATG16L1 restrains IRE1-alpha activity, and augmentation of autophagy in intestinal epithelial cells ameliorates ER stress-induced intestinal inflammation and eases NF-kappa-B overactivation and intestinal epithelial cell death. ER stress, autophagy induction, and spontaneous ileitis emerge from Paneth cell-specific deletion of Xbp1. Adolph et al. (2013) concluded that genetically and environmentally controlled UPR function within Paneth cells may therefore set the threshold for the development of intestinal inflammation upon hypomorphic ATG16L1 function and implicate ileal Crohn disease as a specific disorder of Paneth cells.

The human commensal Bacteroides fragilis delivers immunomodulatory molecules to immune cells via secretion of outer membrane vesicles (OMVs). Chu et al. (2016) found that OMVs require the inflammatory bowel disease (IBD; see 266600)-associated genes ATG16L1 and NOD2 to activate a noncanonical autophagy pathway during protection from colitis. ATG16L1-deficient dendritic cells do not induce regulatory T cells (T(regs)) to suppress mucosal inflammation. Immune cells from human subjects with a major risk variant in ATG16L1 are defective in T(reg) responses to OMVs. Chu et al. (2016) proposed that polymorphisms in susceptibility genes promote disease through defects in 'sensing' protective signals from the microbiome, defining a potentially critical gene-environment etiology for IBD.

In mice, Bel et al. (2017) showed that during bacterial infection with the Salmonella enterica serovar Typhimurium, lysozyme is rerouted via secretory autophagy, an autophagy-based alternative secretion pathway. Secretory autophagy was triggered in Paneth cells by bacteria-induced ER stress, requiring extrinsic signals from innate lymphoid cells, and limited bacterial dissemination. Secretory autophagy was disrupted in Paneth cells of mice harboring a mutation in the autophagy gene Atg16L1 that confers increased risk for Crohn disease in humans. Bel et al. (2017) concluded that their findings identified a role for secretory autophagy in intestinal defense and helped elucidate why Crohn disease is associated with genetic mutations that affect both the ER stress response and autophagy.

Keller et al. (2020) demonstrated that ATG16L1 and other ATG proteins mediate protection against alpha-toxin through the release of ADAM10 (602192) on exosomes (extracellular vesicles of endosomal origin). Bacterial DNA and CpG DNA induced the secretion of ADAM10-bearing exosomes from human cells as well as in mice. Transferred exosomes protected host cells in vitro by serving as scavengers that could bind multiple toxins, and improved the survival of mice infected with MRSA in vivo. Keller et al. (2020) concluded that their findings indicated that ATG proteins mediate a previously unknown form of defense in response to infection, facilitating the release of exosomes that serve as decoys for bacterially produced toxins.


Molecular Genetics

In a genomewide association study of 19,779 nonsynonymous SNPs in 735 individuals with Crohn disease (see IBD10, 611081) and 368 controls, Hampe et al. (2007) identified an A-to-G transition in the ATG16L1 gene (T300A; 610767.0001; rs2241880) that was associated with Crohn disease (CD). The association was replicated in independent CD populations by Rioux et al. (2007) and Franke et al. (2008). In studies in human epithelial cells, Kuballa et al. (2008) demonstrated that the ala300-containing variant had markedly decreased efficiency of Salmonella autophagy compared to the wildtype thr300-containing variant, and suggested that the association of rs2241880 with increased risk of CD is due to impaired bacterial handling and lowered rates of bacterial capture by autophagy.


Animal Model

Cadwell et al. (2008) generated and characterized mice that were hypomorphic for Atg16l1 protein expression and validated conclusions on the basis of studies in mice by analyzing intestinal tissues that they collected from Crohn disease patients carrying the Crohn disease risk allele of ATG16L1. Cadwell et al. (2008) showed that ATG16L1 is a bona fide autophagy protein. Within the ileal epithelium, both ATG16L1 and a second essential autophagy protein, ATG5, are selectively important for the biology of the Paneth cell, a specialized epithelial cell that functions in part by secretion of granule contents containing antimicrobial peptides and other proteins that alter the intestinal environment. Atg16L1- and Atg5-deficient Paneth cells exhibited notable abnormalities in the granule exocytosis pathway. In addition, transcriptional analysis revealed an unexpected gain of function specific to Atg16L1-deficient Paneth cells including increased expression of genes involved in peroxisome proliferator-activated receptor (PPAR) signaling and lipid metabolism, of acute phase reactants and of 2 adipocytokines, leptin (164160) and adiponectin (605441), known to directly influence intestinal injury responses. Importantly, Crohn disease patients homozygous for the ATG16L1 Crohn disease risk allele displayed Paneth cell granule abnormalities similar to those observed in autophagy protein-deficient mice and expressed increased levels of leptin protein. Thus, Cadwell et al. (2008) concluded that ATG16L1, and probably the process of autophagy, have a role within the intestinal epithelium of mice and Crohn disease patients by selective effects on the cell biology and specialized regulatory properties of Paneth cells.

Saitoh et al. (2008) showed that Atg16L1 regulates endotoxin-induced inflammasome activation in mice. Atg16L1 deficiency disrupts the recruitment of the Atg12-Atg5 conjugate to the isolation membrane, resulting in a loss of microtubule-associated protein 1 light chain 3 (LC3; 601242) conjugation to phosphatidylethanolamine. Consequently, both autophagosome formation and degradation of long-lived proteins are severely impaired in Atg16L1-deficient cells. Following stimulation with lipopolysaccharide, a ligand for Toll-like receptor-4 (TLR4; 603030), Atg16L1-deficient macrophages produce high amounts of the inflammatory cytokines IL1-beta (147720) and IL18 (600953). In lipopolysaccharide-stimulated macrophages, Atg16L1 deficiency causes IFN-beta (TRIF; 607601)-dependent activation of caspase-1 (147678), leading to increased production of IL1-beta. Mice lacking Atg16L1 in hematopoietic cells are highly susceptible to dextran sulfate sodium-induced acute colitis, which is alleviated by injection of anti-IL1-beta and IL18 antibodies, indicating the importance of Atg16L1 in the suppression of intestinal inflammation. Saitoh et al. (2008) concluded that ATG16L1 is an essential component of the autophagic machinery responsible for control of the endotoxin-induced inflammatory immune response.

Cadwell et al. (2010) studied mice with hypomorphic Atgl1 protein expression and reduced autophagy that had been raised in an enhanced barrier facility. They detected abnormalities in Paneth cell morphology and granule packaging after infection of these mice with murine norovirus. Subsequently, the response to injury induced by dextran sodium sulfate altered the pathologic picture to resemble Crohn disease. The pathology induced by the virus-plus-susceptibility gene interaction was dependent on Tnf (191160) and Ifng (147570), and it could be prevented by treatment with broad spectrum antibiotics. Mice in the enhanced facility that were not exposed to the virus did not get disease. Cadwell et al. (2010) proposed that the model could explain how virus-plus-susceptibility gene interaction, in combination with environmental insults and commensal bacteria, determines a disease phenotype in hosts carrying common risk alleles for inflammatory disease.

Tschurtschenthaler et al. (2017) observed that mice lacking Atg16l1 in intestinal epithelial cells (IECs) spontaneously developed transmural ileitis phenocopying ileal CD in an age-dependent manner. The ileitis was driven by the ER stress sensor Ire1a, which accumulated in Paneth cells. Humans homozygous for ATG16L1 T300A also exhibited increased IRE1A in intestinal epithelial crypts. Whereas Ire1b (604034) could be protective, hyperactivated Ire1a led to a similar ileitis in younger mice lacking both Atg16l1 and Xbp1 in IECs. Optineurin (OPTN; 602432) interacted with Ire1a, and Optn deficiency amplified Ire1a levels during ER stress. Although there was dysbiosis of the ileal microbiota in mice lacking Atg16l1 and Xbp1 in IECs, accompanied by impaired Paneth cell antimicrobial function, such structural alteration of the microbiota did not trigger ileitis, but rather aggravated dextran sodium sulfate-induced colitis. Tschurtschenthaler et al. (2017) concluded that defective autophagy in IECs may predispose to CD ileitis via impaired clearance of IRE1A aggregates during ER stress.


ALLELIC VARIANTS 1 Selected Example):

.0001   INFLAMMATORY BOWEL DISEASE (CROHN DISEASE) 10, SUSCEPTIBILITY TO

ATG16L1, THR300ALA ({dbSNP rs2241880})
SNP: rs2241880, gnomAD: rs2241880, ClinVar: RCV000001189, RCV000180346, RCV003982820

In a genomewide association study of 19,779 nonsynonymous SNPs in 735 individuals with Crohn disease (see IBD10, 611081) and 368 controls, Hampe et al. (2007) identified a nonsynonymous SNP (A-to-G; rs2241880) in the ATG16L1 gene, resulting in thr300-to-ala (T300A) substitution, that was associated with Crohn disease (CD). The association was replicated in independent populations by Rioux et al. (2007) and Franke et al. (2008). In studies in human epithelial cells, Kuballa et al. (2008) demonstrated that the ala300-containing variant had markedly decreased efficiency in capture of internalized Salmonella within autophagosomes compared to the wildtype thr300-containing variant, and suggested that the association of rs2241880 with increased risk of CD is due to impaired bacterial handling and lowered rates of bacterial capture by autophagy.

In a metaanalysis of 24 studies involving a total of 13,022 CD cases and 17,532 controls, Zhang et al. (2009) confirmed the association of rs2241880 with CD risk in Caucasians (p less than 0.01). No significant association was found in Asians. Zhang et al. (2009) suggested that the G allele is a low-penetrant allele for developing CD in Caucasians.

Murthy et al. (2014) showed that amino acids 296 to 299 of ATG16L1 constitute a caspase cleavage motif and that the T300A variant (T316A in mice) significantly increases ATG16L1 sensitization to CASP3 (600636)-mediated processing. Murthy et al. (2014) observed that death receptor activation or starvation-induced metabolic stress in human and murine macrophages increased degradation of the T300A or T316A variants of ATG16L1, respectively, resulting in diminished autophagy. Knockin mice harboring the T316A variant showed defective clearance of the ileal pathogen Yersinia enterocolitica and an elevated inflammatory cytokine response. In turn, deletion of Casp3 or elimination of the caspase cleavage site by site-directed mutagenesis rescued starvation-induced autophagy and pathogen clearance, respectively. Murthy et al. (2014) concluded that these findings demonstrated that CASP3 activation in the presence of a common risk allele leads to accelerated degradation of ATG16L1, placing cellular stress, apoptotic stimuli, and impaired autophagy in a unified pathway that predisposes to Crohn disease.

Boada-Romero et al. (2016) showed that the T300A polymorphism altered the ability of the ATG16L1 C-terminal WD40 repeat domain to interact with molecules containing a motif that recognizes this region, including TMEM59 (617084), T3JAM (TRAF3IP3; 608255), and DEDD2 (617078). The polymorphism impaired the unconventional autophagic activity of the transmembrane protein TMEM59 and disrupted its normal intracellular trafficking and its ability to engage ATG16L1 in response to S. aureus infection. TMEM59-induced autophagy was blunted in cells expressing fragments generated by caspase processing of ATG16L1 with T300A, whereas canonical autophagy remained unaffected. Boada-Romero et al. (2016) proposed that the T300A polymorphism alters the function of molecules that interact with ATG16L1 via the WD40 repeat domain-binding motif, either by influencing the interaction under nonstressful conditions or by inhibiting their downstream autophagic signaling after caspase-mediated cleavage.


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Contributors:
Ada Hamosh - updated : 06/29/2020
Paul J. Converse - updated : 01/02/2018
Ada Hamosh - updated : 11/28/2017
Ada Hamosh - updated : 09/01/2016
Marla J. F. O'Neill - updated : 7/6/2016
Ada Hamosh - updated : 3/31/2014
Ada Hamosh - updated : 12/13/2013
Paul J. Converse - updated : 6/14/2011
Marla J. F. O'Neill - updated : 7/28/2010
Paul J. Converse - updated : 2/4/2010
Marla J. F. O'Neill - updated : 5/7/2009
Ada Hamosh - updated : 11/26/2008
Marla J. F. O'Neill - updated : 10/28/2008
Ada Hamosh - updated : 7/24/2007
Victor A. McKusick - updated : 5/31/2007
Victor A. McKusick - updated : 5/24/2007

Creation Date:
Patricia A. Hartz : 2/15/2007

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