ATG16L1

ATG16L1
Available structures PDB Ortholog search: PDBe RCSB List of PDB id codes 4GDK, 4GDL, 4NAW, 4TQ0, 5D7G
Identifiers
Aliases	ATG16L1, autophagy related 16-like 1 (S. cerevisiae), APG16L, ATG16A, ATG16L, IBD10, WDR30, autophagy related 16 like 1
External IDs	OMIM: 610767; MGI: 1924290; HomoloGene: 41786; GeneCards: ATG16L1; OMA:ATG16L1 - orthologs
Gene location (Human) Chr. Chromosome 2 (human) Band 2q37.1 Start 233,210,051 bp End 233,295,674 bp
Gene location (Mouse) Chr. Chromosome 1 (mouse) Band 1|1 D Start 87,683,592 bp End 87,720,150 bp
RNA expression pattern Bgee Human Mouse (ortholog) Top expressed in right hemisphere of cerebellum testicle gonad granulocyte right frontal lobe right lobe of thyroid gland left lobe of thyroid gland skin of leg gastrocnemius muscle skin of abdomen Top expressed in neural layer of retina secondary oocyte primary oocyte granulocyte motor neuron superior frontal gyrus primary visual cortex right ventricle transitional epithelium of urinary bladder dentate gyrus of hippocampal formation granule cell More reference expression data BioGPS More reference expression data
Gene ontology Molecular function ubiquitin-like protein transferase activity protein binding identical protein binding GTPase binding Cellular component cytoplasm autophagosome axoneme cytosol phagophore assembly site membrane autophagosome membrane membrane Biological process protein transport autophagy negative stranded viral RNA replication protein homooligomerization macroautophagy autophagosome assembly protein localization to phagophore assembly site protein lipidation involved in autophagosome assembly xenophagy positive regulation of autophagy Sources:Amigo / QuickGO
Orthologs Species Human Mouse Entrez 55054 77040 Ensembl ENSG00000281089 ENSG00000085978 ENSMUSG00000026289 UniProt Q676U5 Q8C0J2 RefSeq (mRNA) NM_001190266 NM_001190267 NM_017974 NM_030803 NM_198890 NM_001363742 NM_001205391 NM_001205392 NM_029846 RefSeq (protein) NP_001177195 NP_001177196 NP_060444 NP_110430 NP_942593 NP_001350671 NP_060444.3 NP_001192320 NP_001192321 NP_084122 Location (UCSC) Chr 2: 233.21 – 233.3 Mb Chr 1: 87.68 – 87.72 Mb PubMed search
Wikidata
View/Edit Human View/Edit Mouse

Autophagy related 16 like 1 is a protein that in humans is encoded by the ATG16L1 gene. This protein is characterized as a subunit of the autophagy-related ATG12-ATG5/ATG16 complex and is essentially important for the LC3 (ATG8) lipidation and autophagosome formation. This complex localizes to the membrane and is released just before or after autophagosome completion.

Furthermore, ATG16L1 appears to have other autophagy-independent functions, e.g., intracellular membrane trafficking regulation and inflammation. Autophagy in general plays a crucial role in pathways leading to innate and adaptive immunity activation. That is why many autophagy-related proteins, including ATG16L1, their gene expression and its role in autoimmune diseases are studied in-depth nowadays.

Function

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. Several proteins which interact with ATG16L have been identified to reveal its function. It appears that ATGL16L has an important role not only in autophagy but also in xenophagy for example during a bacterial infection, in antigen presentation in human B cells, plasma membrane repair in mouse embryonic fibroblasts, hormone secretion and in alcohol-induced sedation response in Drosophila.

Structure

ATG16L1 protein consists of three main domains - N-terminal region which contains an alpha-helix required for binding to ATG5 ubiquitin-folds, a middle region (coiled-coil domain, CCD), and a domain made of seven WD40 repeats, that forms a β-propeller, found in its C-terminal part. Polymorphisms and mutations in these domains are considered to be associated with several diseases.

Due to present models, ATG16L1 is supposed to exist in ~800 kDa complexes which contain ATG12-ATG5 and several ATG16L1 dimers. These dimers are composed mostly of a CCD region of the protein and ATG5 binding site. The middle region is considered to be essential for the ATG16L1 function. Mice with CCD deletions exhibited phenotypic abnormalities as well as neonatal fatality, though non of these were observed in WD40 region deletion phenotype. Surprisingly, overexpression of CCD, as well as deletion, leads to an inhibition of autophagosome formation.

Clinical significance

ATG16L1 is expressed in the colon, intestinal cells, leukocytes and spleen. Recent studies have shown that mutations in the ATG16L1 gene may be linked to Crohn's disease. A coding polymorphism in ATG16L1 gene is considered to be a risk factor for Crohn's disease development as well as ATG16L2. ATG16L1 appears to be an essential protein for the function of intestinal stem cells, morphological structure of intestinal cells and granule exocytosis pathway of the Paneth cells in animal models.

Bacteria invasion leads to ATG16L1 recruiting by NOD1 and NOD2. This results in autophagy in RIP2/NF-κB independent manner. It is also known that NOD2 interacts with ATG16L, ATG5 and ATG7 and provides antibacterial immune response through autophagy induction and MHC class II antigen-specific CD4+ T cell responses. It has also been shown that low levels of ATG16L1 result in lower ATG16L1-NOD2 complex formation, which is crucial for bacterial autophagy in the bacterial entry site. Inhibition of autophagy leads to a NOD2 signaling through RIP2 kinase and induction of cytokine responses. This promotes an increase in mRNA expression of highly potent pro-inflammatory cytokines as interkleukin-1 (IL-1β).

ATG16L1 also plays a role in viral infections. Through autophagy viral particles are delivered into the lysosome degradation pathway and interrogate with a specific type of pattern recognition receptor to initiate type I interferon (IFN-I) expression and viral clearance. Interestingly, ATG5-ATG12/ATG16L1 complex negatively regulates RIG-I-like receptor pathway and IFN-I expression. A mouse with a deletion in one of these genes appears to be resistant to virus replication. It is most likely due to an unregulated overexpression of IFN-I, which interferes with the virus life cycle.

ATG16L2 is a related protein, which is also highly conserved (both ATG16L1 and 2 share 94 and 83% sequence identity). It has been shown that changes in ATG16L2 expression are correlated with Multiple Sclerosis (MS) and can be used as a serum biomarker of the disease and specifically for the prediction of relapse rates. Interestingly ATG16L2 mRNA expression was significantly reduced (~4-fold lower) in T cells isolated from the peripheral blood of MS patients in comparison to healthy age-matched controls, which may reflect their abnormal activation.

Further reading

• Mizushima N, Kuma A, Kobayashi Y, Yamamoto A, Matsubae M, Takao T, et al. (May 2003). "Mouse Apg16L, a novel WD-repeat protein, targets to the autophagic isolation membrane with the Apg12-Apg5 conjugate". Journal of Cell Science. 116 (Pt 9): 1679–88. doi:10.1242/jcs.00381. PMID 12665549.
• Clark HF, Gurney AL, Abaya E, Baker K, Baldwin D, Brush J, et al. (October 2003). "The secreted protein discovery initiative (SPDI), a large-scale effort to identify novel human secreted and transmembrane proteins: a bioinformatics assessment". Genome Research. 13 (10): 2265–70. doi:10.1101/gr.1293003. PMC 403697. PMID 12975309.
• Bouwmeester T, Bauch A, Ruffner H, Angrand PO, Bergamini G, Croughton K, et al. (February 2004). "A physical and functional map of the human TNF-alpha/NF-kappa B signal transduction pathway". Nature Cell Biology. 6 (2): 97–105. doi:10.1038/ncb1086. PMID 14743216. S2CID 11683986.
• Zheng H, Ji C, Li J, Jiang H, Ren M, Lu Q, et al. (August 2004). "Cloning and analysis of human Apg16L". DNA Sequence. 15 (4): 303–5. doi:10.1080/10425170400004104. PMID 15620219. S2CID 33446132.
• Kimura K, Wakamatsu A, Suzuki Y, Ota T, Nishikawa T, Yamashita R, et al. (January 2006). "Diversification of transcriptional modulation: large-scale identification and characterization of putative alternative promoters of human genes". Genome Research. 16 (1): 55–65. doi:10.1101/gr.4039406. PMC 1356129. PMID 16344560.
• Hampe J, Franke A, Rosenstiel P, Till A, Teuber M, Huse K, et al. (February 2007). "A genome-wide association scan of nonsynonymous SNPs identifies a susceptibility variant for Crohn disease in ATG16L1". Nature Genetics. 39 (2): 207–11. doi:10.1038/ng1954. PMID 17200669. S2CID 24615261.
• Ewing RM, Chu P, Elisma F, Li H, Taylor P, Climie S, et al. (2007). "Large-scale mapping of human protein-protein interactions by mass spectrometry". Molecular Systems Biology. 3 (1): 89. doi:10.1038/msb4100134. PMC 1847948. PMID 17353931.
• Prescott NJ, Fisher SA, Franke A, Hampe J, Onnie CM, Soars D, et al. (May 2007). "A nonsynonymous SNP in ATG16L1 predisposes to ileal Crohn's disease and is independent of CARD15 and IBD5". Gastroenterology. 132 (5): 1665–71. doi:10.1053/j.gastro.2007.03.034. PMID 17484864.
• Yamazaki K, Onouchi Y, Takazoe M, Kubo M, Nakamura Y, Hata A (2007). "Association analysis of genetic variants in IL23R, ATG16L1 and 5p13.1 loci with Crohn's disease in Japanese patients". Journal of Human Genetics. 52 (7): 575–583. doi:10.1007/s10038-007-0156-z. PMID 17534574.
• Baldassano RN, Bradfield JP, Monos DS, Kim CE, Glessner JT, Casalunovo T, et al. (August 2007). "Association of the T300A non-synonymous variant of the ATG16L1 gene with susceptibility to paediatric Crohn's disease". Gut. 56 (8): 1171–3. doi:10.1136/gut.2007.122747. PMC 1955510. PMID 17625155.

External links

• Human ATG16L1 genome location and ATG16L1 gene details page in the UCSC Genome Browser.

This article incorporates text from the United States National Library of Medicine, which is in the public domain.