The multifaceted functions of ATG16L1 in autophagy and related processes

Gammoh, Noor

doi:10.1242/jcs.249227

Cited by 50 publications

(30 citation statements)

References 122 publications

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“…ATG16L1 emerges as an important hub for specific cargo to connect to the autophagy machinery (reviewed by Gammoh, 2020 ). Besides its role in LC3 lipidation, it has binding sites for ubiquitin, FIP200 and WIPI2, phosphoinositides, and generally for membranes.…”

Section: Introductionmentioning

confidence: 99%

Rabaptin5 targets autophagy to damaged endosomes and Salmonella vacuoles via FIP200 and ATG16L1

et al. 2021

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Selective autophagy of damaged organelles is important to maintain cellular homeostasis. The mechanisms how autophagy selects specific targets is often poorly understood. Rabaptin5 was previously known as a major regulator of early endosome identity and maturation. Here, we identify two novel Rabaptin5 interactors: FIP200, a subunit of the ULK1 autophagy initiator complex, and ATG16L1, a central component of the E3-like enzyme in LC3 lipidation. Autophagy of early endosomes damaged by chloroquine or monensin treatment requires Rabaptin5 and particularly a short sequence motif that binds to the WD domain of ATG16L1. Rabapt-in5 and its interaction with ATG16L1 further contributes to the autophagic elimination of Salmonella enterica early after infection, when it resides in phagosomes with early endosomal characteristics. Our results demonstrate a novel function of Rabaptin5 in quality control of early endosomes in the selective targeting of autophagy to damaged early endosomes and phagosomes.

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Section: Introductionmentioning

confidence: 99%

Rabaptin5 targets autophagy to damaged endosomes and Salmonella vacuoles via FIP200 and ATG16L1

et al. 2021

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“…In addition, it also should have a LIR or UIM motif to interact with ATG8 family proteins for anchoring autophagic cargoes around nascent phagophores. Previous functional studies have well established that mammalian ATG16L1 can function as an adaptor to speci cally recognize invading pathogens or pathogen-containing vacuoles through its C-terminal WD40 repeats domain to mediate xenophagy processes 38,39,41,42 . Meanwhile, ATG16L1 can directly interact with RB1CC1 to recruit the ULK complex 36,37 .…”

Section: Discussionmentioning

confidence: 99%

“…Unlike its yeast homolog ATG16, the C-terminal region of ATG16L1 contains an additional WD40 repeats domain (Fig. 1a), which can speci cally recognize invading pathogens or pathogencontaining vacuoles by binding to relevant proteins including ubiquitin 38 , the complement protein C3 39,40 , and V-ATPase 41 , thereby endowing ATG16L1 with speci c functions in antibacterial selective autophagy (also called xenophagy) 42 . Notably, in addition to its essential role in canonical autophagy, the interaction between ATG16L1 and WIPI2b is also required for xenophagy 10 .…”

Section: Read Full License Introductionmentioning

confidence: 99%

Mechanistic insights into the distinct functions of ATG16L1 in canonical autophagy and selective autophagy

Pan

Gong

Wang

et al. 2021

Preprint

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Macroautophagy plays crucial roles in the regulation of cellular physiology, and requires de novo synthesis of double-membrane autophagosomes. The formation of autophagosomes entails the lipidation of ATG8 family proteins catalyzed by the ATG12 ~ ATG5-ATG16L1 complex, which is recruited to the pre-autophagosomal membrane through a direct interaction between ATG16L1 and WIPI2b. In addition, ATG16L1 can function as an adaptor to specifically recognize invading pathogens to mediate antibacterial selective autophagy, and the T300A polymorphism of ATG16L1 has been associated with the Crohn's disease, an inflammatory bowel disease mainly caused by the defect in antibacterial autophagy. However, the molecular mechanism governing the interaction of ATG16L1 with WIPI2b and the precise role of ATG16L1 in selective autophagy remain elusive. Here, we reported the atomic structure of the WIPI2b/ATG16L1 complex, and elucidated the mechanistic basis underpinning the recruitment of ATG16L1 by WIPI2b. Moreover, we discovered that the FIR motif of ATG16L1 not only can directly interact with RB1CC1 Claw domain, but also can selectively recognize mammalian ATG8 family proteins. We determined the high-resolution crystal structures of ATG16L1 FIR in complex with RB1CC1 Claw and GABARAPL1 respectively, and uncovered the molecular mechanism underlying the interactions of ATG16L1 with RB1CC1 and ATG8 family proteins. On this basis, we proposed the concept that ATG16L1 can be categorized as a potential autophagy receptor. In all, our findings provide novel mechanistic insights into the interactions of ATG16L1 with WIPI2b, RB1CC1 and ATG8 family proteins, and are valuable for further understanding the distinct functions of ATG16L1 in autophagy.

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“…Therefore, cellular autophagy is often associated with inflammation but acts in an anti-inflammatory manner [60,61] (see also Section 4.1). Ablation of the essential autophagy-related gene ATG16L1 in mice causes an inflammatory phenotype characterized by high levels of IL-1β and -18 due to increased inflammasome activation (see Section 4.1) [62,63].…”

Section: P62 Is a Cargo Receptor For Autophagymentioning

confidence: 99%

The Pathways Underlying the Multiple Roles of p62 in Inflammation and Cancer

et al. 2021

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p62 is a highly conserved, multi-domain, and multi-functional adaptor protein critically involved in several important cellular processes. Via its pronounced domain architecture, p62 binds to numerous interaction partners, thereby influencing key pathways that regulate tissue homeostasis, inflammation, and several common diseases including cancer. Via binding of ubiquitin chains, p62 acts in an anti-inflammatory manner as an adaptor for the auto-, xeno-, and mitophagy-dependent degradation of proteins, pathogens, and mitochondria. Furthermore, p62 is a negative regulator of inflammasome complexes. The transcription factor Nrf2 regulates expression of a bundle of ROS detoxifying genes. p62 activates Nrf2 by interaction with and autophagosomal degradation of the Nrf2 inhibitor Keap1. Moreover, p62 activates mTOR, the central kinase of the mTORC1 sensor complex that controls cell proliferation and differentiation. Through different mechanisms, p62 acts as a positive regulator of the transcription factor NF-κB, a central player in inflammation and cancer development. Therefore, p62 represents not only a cargo receptor for autophagy, but also a central signaling hub, linking several important pro- and anti-inflammatory pathways. This review aims to summarize knowledge about the molecular mechanisms underlying the roles of p62 in health and disease. In particular, different types of tumors are characterized by deregulated levels of p62. The elucidation of how p62 contributes to inflammation and cancer progression at the molecular level might promote the development of novel therapeutic strategies.

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The multifaceted functions of ATG16L1 in autophagy and related processes

Cited by 50 publications

References 122 publications

Rabaptin5 targets autophagy to damaged endosomes and Salmonella vacuoles via FIP200 and ATG16L1

Rabaptin5 targets autophagy to damaged endosomes and Salmonella vacuoles via FIP200 and ATG16L1

Mechanistic insights into the distinct functions of ATG16L1 in canonical autophagy and selective autophagy

The Pathways Underlying the Multiple Roles of p62 in Inflammation and Cancer

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