# ATG16L1

## Overview
ATG16L1 is a gene that encodes the autophagy-related protein 16-like 1, a critical component of the autophagy machinery in human cells. This protein is involved in the formation of autophagosomes, which are essential for the degradation and recycling of cellular components. The ATG16L1 protein is characterized by its three major domains: the N-terminal ATG5-binding domain, a central coiled-coil domain, and a C-terminal WD40 domain, each contributing to its role in autophagy and other cellular processes (Bajagic2017Structure; Archna2017Identification). Beyond its canonical role in autophagy, ATG16L1 is implicated in various cellular functions, including inflammation regulation, intracellular trafficking, and plasma membrane repair (Hamaoui2021ATG16L1; Gammoh2020The). Mutations in the ATG16L1 gene, such as the T300A polymorphism, have been associated with diseases like Crohn's disease and gastric cancer, highlighting its clinical significance (Lassen2014Atg16L1; Burada2015ATG16L1).

## Structure
The ATG16L1 protein is a crucial component of the autophagy machinery, consisting of 607 amino acids and featuring three major domains: the N-terminal ATG5-binding domain (ATG5BD), a central coiled-coil domain (CCD), and a C-terminal WD40 domain (Bajagic2017Structure; Archna2017Identification). The ATG5BD is responsible for binding with the ATG12~ATG5 conjugate, facilitating the formation of the ATG12~ATG5/ATG16L1 complex, which functions as an E3-ligase essential for autophagosome biogenesis (Bajagic2017Structure).

The coiled-coil domain is important for protein oligomerization and interaction with other autophagy-related proteins, such as WIPI2 and Rab33 (Bajagic2017Structure). The Rab33B binding site is located within residues 141-265, which includes part of the coiled-coil domain (MetjeSprink2020Crystal).

The C-terminal WD40 domain, unique to mammalian ATG16L1, is involved in protein-protein interactions related to alternative autophagy functions, such as inflammatory control and xenophagy (Bajagic2017Structure). This domain is characterized by a seven-bladed propeller structure, with interaction surfaces that facilitate binding with various proteins (Bajagic2017Structure). The WD40 domain is not essential for canonical autophagy but is crucial for selective autophagy (Bajagic2017Structure).

Post-translational modifications, such as phosphorylation, influence the function of ATG16L1 in autophagy. The T300A mutation, associated with Crohn's disease, is located outside the WD40 domain and may affect protein interactions (Bajagic2017Structure).

## Function
The ATG16L1 gene encodes a protein that is a crucial component of the autophagy machinery in human cells. It forms part of the ATG12-ATG5/ATG16L1 complex, which is essential for the lipidation of LC3, a key step in autophagosome formation. This complex acts as a noncanonical E3 ligase, facilitating the attachment of LC3 to phosphatidylethanolamine, thereby anchoring LC3 to the target membrane, which is vital for the growth and closure of the phagophore (Hamaoui2021ATG16L1). ATG16L1 is involved in the formation of autophagosomes, structures that engulf and degrade cellular components, playing a role in recycling organelles and protein aggregates, controlling cell signaling, metabolism, and defending against pathogens (Hamaoui2021ATG16L1).

Beyond its role in autophagy, ATG16L1 has functions independent of the lipidation reaction, contributing to cell homeostasis by acting as a brake on inflammation and regulating intracellular traffic (Hamaoui2021ATG16L1). It is involved in exocytosis, particularly in exosome production, which is crucial for cell-to-cell communication and has implications in immune response, tumor metastasis, and neurodegeneration (Gammoh2020The). ATG16L1 also plays a role in plasma membrane repair upon bacterial toxin-mediated damage, promoting lysosomal exocytosis (Hamaoui2021ATG16L1).

## Clinical Significance
Mutations and polymorphisms in the ATG16L1 gene have been implicated in several diseases, most notably Crohn's disease (CD), a chronic inflammatory condition of the gastrointestinal tract. The T300A polymorphism in ATG16L1 is associated with an increased risk of developing CD, particularly ileal CD, due to its impact on autophagy and immune responses. This variant leads to decreased selective autophagy, altered cytokine signaling, and reduced antibacterial defense, contributing to the pathogenesis of CD (Lassen2014Atg16L1; Prescott2007A). The rs2241880G allele of ATG16L1 is also linked to adult-onset CD, with a specific association with ileal disease (Van2008Autophagy).

In addition to CD, the ATG16L1 T300A polymorphism has been studied in the context of gastric cancer. Individuals carrying the AG or GG genotypes of this polymorphism have a lower risk of developing gastric cancer, particularly non-cardia and intestinal types, compared to those with the AA genotype (Burada2015ATG16L1).

The ATG16L1 gene also plays a role in the progression of chronic HIV-1 infection. The rs6861(TT) genotype is associated with prolonged survival and improved T-cell immunity in HIV-1-infected individuals, suggesting a protective effect against disease progression (Schreurs2024Autophagyenhancing).

## Interactions
ATG16L1 is a crucial component of the autophagy machinery, participating in various protein interactions essential for autophagosome formation. It forms a complex with ATG5 and ATG12, known as the ATG12-ATG5-ATG16L1 complex, which is vital for the recruitment of the ATG5-ATG12 conjugate to the phagophore, a critical step in autophagosome biogenesis (Gammoh2020The). ATG16L1 interacts with the FIP200 protein, a component of the ULK1 complex, which is necessary for targeting ATG16L1 to the isolation membrane during autophagosome formation (Nishimura2013FIP200). The interaction between ATG16L1 and FIP200 is mediated by the FIP200-interacting region (FIR) of ATG16L1, which is crucial for autophagic flux and the recruitment of the ULK complex (Pan2024Molecular).

ATG16L1 also interacts with the ATG8 family proteins, including GABARAPL1 and LC3C, through its FIR motif, which can bind to the canonical AIM-binding groove of these proteins (Pan2024Molecular). These interactions are characterized by both polar and hydrophobic interactions, involving key residues of ATG16L1. The interactions with ATG8 family proteins are mutually exclusive with FIP200 binding, suggesting a competitive binding mechanism (Pan2024Molecular).


## References


[1. (Hamaoui2021ATG16L1) Daniel Hamaoui and Agathe Subtil. Atg16l1 functions in cell homeostasis beyond autophagy. The FEBS Journal, 289(7):1779–1800, April 2021. URL: http://dx.doi.org/10.1111/febs.15833, doi:10.1111/febs.15833. This article has 21 citations.](https://doi.org/10.1111/febs.15833)

[2. (Gammoh2020The) Noor Gammoh. The multifaceted functions of atg16l1 in autophagy and related processes. Journal of Cell Science, October 2020. URL: http://dx.doi.org/10.1242/jcs.249227, doi:10.1242/jcs.249227. This article has 43 citations and is from a domain leading peer-reviewed journal.](https://doi.org/10.1242/jcs.249227)

[3. (Prescott2007A) Natalie J. Prescott, Sheila A. Fisher, Andre Franke, Jochen Hampe, Clive M. Onnie, Dianne Soars, Richard Bagnall, Muddassar M. Mirza, Jeremy Sanderson, Alastair Forbes, John C. Mansfield, Cathryn M. Lewis, Stefan Schreiber, and Christopher G. Mathew. A nonsynonymous snp in atg16l1 predisposes to ileal crohn’s disease and is independent of card15 and ibd5. Gastroenterology, 132(5):1665–1671, May 2007. URL: http://dx.doi.org/10.1053/j.gastro.2007.03.034, doi:10.1053/j.gastro.2007.03.034. This article has 226 citations and is from a highest quality peer-reviewed journal.](https://doi.org/10.1053/j.gastro.2007.03.034)

[4. (Schreurs2024Autophagyenhancing) Renée R. C. E. Schreurs, Athanasios Koulis, Thijs Booiman, Brigitte Boeser-Nunnink, Alexandra P. M. Cloherty, Anusca G. Rader, Kharishma S. Patel, Neeltje A. Kootstra, and Carla M. S. Ribeiro. Autophagy-enhancing atg16l1 polymorphism is associated with improved clinical outcome and t-cell immunity in chronic hiv-1 infection. Nature Communications, March 2024. URL: http://dx.doi.org/10.1038/s41467-024-46606-z, doi:10.1038/s41467-024-46606-z. This article has 0 citations and is from a highest quality peer-reviewed journal.](https://doi.org/10.1038/s41467-024-46606-z)

[5. (Bajagic2017Structure) Milica Bajagic, Archna Archna, Petra Büsing, and Andrea Scrima. Structure of the wd40‐domain of human atg16l1. Protein Science, 26(9):1828–1837, July 2017. URL: http://dx.doi.org/10.1002/pro.3222, doi:10.1002/pro.3222. This article has 22 citations and is from a peer-reviewed journal.](https://doi.org/10.1002/pro.3222)

[6. (Burada2015ATG16L1) Florin Burada, Marius Eugen Ciurea, Raluca Nicoli, Ioana Streata, Ionica Dan Vilcea, Ion Rogoveanu, and Mihai Ioana. Atg16l1 t300a polymorphism is correlated with gastric cancer susceptibility. Pathology & Oncology Research, 22(2):317–322, November 2015. URL: http://dx.doi.org/10.1007/s12253-015-0006-9, doi:10.1007/s12253-015-0006-9. This article has 26 citations.](https://doi.org/10.1007/s12253-015-0006-9)

[7. (Van2008Autophagy) J. Van Limbergen, R. K. Russell, E. R. Nimmo, H. E. Drummond, L. Smith, N. H. Anderson, G. Davies, P. M. Gillett, P. McGrogan, L. T. Weaver, W. M. Bisset, G. Mahdi, I. D. Arnott, D. C. Wilson, and J. Satsangi. Autophagy gene atg16l1 influences susceptibility and disease location but not childhood-onset in crohnʼs disease in northern europe. Inflammatory Bowel Diseases, 14(3):338–346, March 2008. URL: http://dx.doi.org/10.1002/ibd.20340, doi:10.1002/ibd.20340. This article has 0 citations and is from a domain leading peer-reviewed journal.](https://doi.org/10.1002/ibd.20340)

[8. (Archna2017Identification) Archna Archna and Andrea Scrima. Identification, biochemical characterization and crystallization of the central region of human atg16l1. Acta Crystallographica Section F Structural Biology Communications, 73(10):560–567, September 2017. URL: http://dx.doi.org/10.1107/s2053230x17013280, doi:10.1107/s2053230x17013280. This article has 4 citations.](https://doi.org/10.1107/s2053230x17013280)

[9. (MetjeSprink2020Crystal) Janina Metje-Sprink, Johannes Groffmann, Piotr Neumann, Brigitte Barg-Kues, Ralf Ficner, Karin Kühnel, Amanda M. Schalk, and Beyenech Binotti. Crystal structure of the rab33b/atg16l1 effector complex. Scientific Reports, July 2020. URL: http://dx.doi.org/10.1038/s41598-020-69637-0, doi:10.1038/s41598-020-69637-0. This article has 13 citations and is from a peer-reviewed journal.](https://doi.org/10.1038/s41598-020-69637-0)

[10. (Nishimura2013FIP200) Taki Nishimura, Takeshi Kaizuka, Ken Cadwell, Mayurbhai H Sahani, Tatsuya Saitoh, Shizuo Akira, Herbert W Virgin, and Noboru Mizushima. Fip200 regulates targeting of atg16l1 to the isolation membrane. EMBO reports, 14(3):284–291, February 2013. URL: http://dx.doi.org/10.1038/embor.2013.6, doi:10.1038/embor.2013.6. This article has 163 citations and is from a highest quality peer-reviewed journal.](https://doi.org/10.1038/embor.2013.6)

11. (Pan2024Molecular) Molecular bases of the interactions of ATG16L1 with FIP200 and ATG8 family proteins. This article has 0 citations.

[12. (Lassen2014Atg16L1) Kara G. Lassen, Petric Kuballa, Kara L. Conway, Khushbu K. Patel, Christine E. Becker, Joanna M. Peloquin, Eduardo J. Villablanca, Jason M. Norman, Ta-Chiang Liu, Robert J. Heath, Morgan L. Becker, Lola Fagbami, Heiko Horn, Johnathan Mercer, Omer H. Yilmaz, Jacob D. Jaffe, Alykhan F. Shamji, Atul K. Bhan, Steven A. Carr, Mark J. Daly, Herbert W. Virgin, Stuart L. Schreiber, Thaddeus S. Stappenbeck, and Ramnik J. Xavier. Atg16l1 t300a variant decreases selective autophagy resulting in altered cytokine signaling and decreased antibacterial defense. Proceedings of the National Academy of Sciences, 111(21):7741–7746, May 2014. URL: http://dx.doi.org/10.1073/pnas.1407001111, doi:10.1073/pnas.1407001111. This article has 298 citations.](https://doi.org/10.1073/pnas.1407001111)