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Several proteins which interact with ATG16L have been identified to reveal its function. It appears to be, 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.[1]

Structure[editovat | editovat zdroj]

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 seven WD40 domains 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 several dimers. These dimers are composed mostly of a CCD region of the protein and ATG5 binding. 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.[2]

Mutations in the ATG16L1 gene may be linked to Crohn's disease. A coding polymorphism in atgl1 gene is considered to be a risk factor for the Crohn's disease development as well as atgl2. ATG16 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.[1] 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).[3] [4]

ATG16L1 also plays a role in viral infections. Through autophagy viral particles are delivered into 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-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 is known to interfere with virus life cycle. [5]

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 the decrease in ATGL2 expression is correlated with Multiple Sclerosis and can be used as a marker of the disease and specifically for the prediction of relapse rates.

  1. a b XIONG, Qiuhong; LI, Wenjing; LI, Ping. The Role of ATG16 in Autophagy and The Ubiquitin Proteasome System. Cells. 2018-12-20, roč. 8, čís. 1. PMID: 30577509 PMCID: PMC6356889. Dostupné online [cit. 2021-06-23]. ISSN 2073-4409. DOI 10.3390/cells8010002. PMID 30577509. 
  2. GAMMOH, Noor. The multifaceted functions of ATG16L1 in autophagy and related processes. Journal of Cell Science. 2020-10-30, roč. 133, čís. jcs249227. Dostupné online [cit. 2021-06-24]. ISSN 0021-9533. DOI 10.1242/jcs.249227. 
  3. ZHOU, Xu-Jie; ZHANG, Hong. Autophagy in immunity. Autophagy. 2012-09-14, roč. 8, čís. 9, s. 1286–1299. PMID: 22878595. Dostupné online [cit. 2021-06-23]. ISSN 1554-8627. DOI 10.4161/auto.21212. PMID 22878595. 
  4. DERETIC, Vojo. Autophagy in Infection. Current opinion in cell biology. 2010-4, roč. 22, čís. 2, s. 252–262. PMID: 20116986 PMCID: PMC2866841. Dostupné online [cit. 2021-06-25]. ISSN 0955-0674. DOI 10.1016/j.ceb.2009.12.009. PMID 20116986. 
  5. HAMAOUI, Daniel; SUBTIL, Agathe. ATG16L1 functions in cell homeostasis beyond autophagy. The FEBS Journal. Roč. n/a, čís. n/a. Dostupné online [cit. 2021-06-25]. ISSN 1742-4658. DOI 10.1111/febs.15833. (anglicky)