STING induces LC3B lipidation onto single-membrane vesicles via the V-ATPase and ATG16L1-WD40 domain

Fischer, Tara D.; Wang, Chunxin; Padman, Benjamin Scott; Lazarou, Michael; Youle, Richard J.

doi:10.1083/jcb.202009128

Cited by 117 publications

(150 citation statements)

References 63 publications

(111 reference statements)

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“…The scenario proposed in that study involved the ATG5/ ATG16L1-dependent dissociation of a subunit of the V-ATPase, and its degradation in exosomes, thereby controlling the acidification of exosomes and their release [108]. The interaction between the WDD and the V-ATPase observed in the context of an infection and discussed in ATG16L1's WDD recruits the LC3conjugation machinery to lipidate PE at specific single membranes might be implicated in the mechanism by which ATG5 and ATG16L1 regulate exosome maturation and release [70,77] Finally, recent work in the ameba D. discoideum not only confirmed the essential function of the ATG12-ATG5/ATG16L1 complex in canonical autophagy, but also supported an autophagy-independent function of the complex and its individual components in the regulation of phagocytosis and pinocytosis. The data indicate that engagement of the complex in endocytic events might have evolved early [109].…”

Section: Loss Of Atg16l1 or Expression Of The T300a Variant Affects Ementioning

confidence: 99%

ATG16L1 functions in cell homeostasis beyond autophagy

Hamaoui

Subtil

2021

The FEBS Journal

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Atg16-like (ATG16L) proteins were identified in higher eukaryotes for their resemblance to Atg16, a yeast protein previously characterized as a subunit of the Atg12-Atg5/Atg16 complex. In yeast, this complex catalyzes the lipidation of Atg8 on pre-autophagosomal structures and is therefore required for the formation of autophagosomes. In higher eukaryotes, ATG16L1 is also almost exclusively present as part of an ATG12-ATG5/ATG16L1 complex and has the same essential function in autophagy. However, ATG16L1 is three times bigger than Atg16. It displays, in particular, a carboxy-terminal extension, including a WD40 domain, which provides a platform for interaction with a variety of proteins, and allows for the recruitment of the ATG12-ATG5/ATG16L1 complex to membranes under different contexts. Furthermore, detailed analyses at the cellular level have revealed that some of the ATG16L1-driven activities are independent of the lipidation reaction catalyzed by the ATG12-ATG5/ATG16L1 complex. At the organ level, the use of mice that are hypomorphic for Atg16l1, or with cell-specific ablation of its expression, revealed a large panel of consequences of ATG16L1 dysfunctions. In this review, we recapitulate the current knowledge on ATG16L1 expression and functions. We emphasize, in particular, how it broadly acts as a brake on inflammation, thereby contributing to maintaining cell homeostasis. We also report on independent studies that converge to show that ATG16L1 is an important player in the regulation of intracellular traffic. Overall, autophagy-independent functions of ATG16L1 probably account for more of the phenotypes associated with ATG16L1 deficiencies than currently appreciated.

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Section: Loss Of Atg16l1 or Expression Of The T300a Variant Affects Ementioning

confidence: 99%

ATG16L1 functions in cell homeostasis beyond autophagy

Hamaoui

Subtil

2021

The FEBS Journal

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“…However, the C-terminal membrane-binding region is present only in the β-isomer of ATG16L1, indicating that ATG16L1 isoforms mechanistically differentiate between different LC3B lipidation mechanisms ( 72 ). The STING-mediated LC3B lipidation occurs onto single-membrane perinuclear vesicles mediated by ATG16L1 through its WD40 domain, which bypasses the requirement of canonical upstream autophagy machinery ( 73 , 74 ). The WD repeat-containing C-terminal domain (WD40 CTD) of ATG16L1 is crucial for LC3 recruitment to endolysosomal membranes during non-canonical autophagy, but not for canonical autophagy ( 74 ) Bafliomycin A1 inhibits the vacuolar ATPase (V-ATPase) through binding to it.…”

Section: Cgas-sting-based Host Cell Dna Recognitionmentioning

confidence: 99%

“…The WD repeat-containing C-terminal domain (WD40 CTD) of ATG16L1 is crucial for LC3 recruitment to endolysosomal membranes during non-canonical autophagy, but not for canonical autophagy ( 74 ) Bafliomycin A1 inhibits the vacuolar ATPase (V-ATPase) through binding to it. A bacterial product SpoF also inhibits V-ATPase via catalytically modifying it to prevent LC3B lipidation via ATG16L1 ( 73 ). Thus cGAS-STING signaling also induces V-ATPase-dependent LC3B lipidation to mediate cell-autonomous host defense that is different from LC3B lipidation onto double-membrane autophagosome ( 73 ).…”

Section: Cgas-sting-based Host Cell Dna Recognitionmentioning

confidence: 99%

“…A bacterial product SpoF also inhibits V-ATPase via catalytically modifying it to prevent LC3B lipidation via ATG16L1 ( 73 ). Thus cGAS-STING signaling also induces V-ATPase-dependent LC3B lipidation to mediate cell-autonomous host defense that is different from LC3B lipidation onto double-membrane autophagosome ( 73 ).…”

Section: Cgas-sting-based Host Cell Dna Recognitionmentioning

confidence: 99%

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The Trinity of cGAS, TLR9, and ALRs Guardians of the Cellular Galaxy Against Host-Derived Self-DNA

Kumar

2021

Front. Immunol.

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The immune system has evolved to protect the host from the pathogens and allergens surrounding their environment. The immune system develops in such a way to recognize self and non-self and develops self-tolerance against self-proteins, nucleic acids, and other larger molecules. However, the broken immunological self-tolerance leads to the development of autoimmune or autoinflammatory diseases. Pattern-recognition receptors (PRRs) are expressed by immunological cells on their cell membrane and in the cytosol. Different Toll-like receptors (TLRs), Nod-like receptors (NLRs) and absent in melanoma-2 (AIM-2)-like receptors (ALRs) forming inflammasomes in the cytosol, RIG (retinoic acid-inducible gene)-1-like receptors (RLRs), and C-type lectin receptors (CLRs) are some of the PRRs. The DNA-sensing receptor cyclic GMP–AMP synthase (cGAS) is another PRR present in the cytosol and the nucleus. The present review describes the role of ALRs (AIM2), TLR9, and cGAS in recognizing the host cell DNA as a potent damage/danger-associated molecular pattern (DAMP), which moves out to the cytosol from its housing organelles (nucleus and mitochondria). The introduction opens with the concept that the immune system has evolved to recognize pathogens, the idea of horror autotoxicus, and its failure due to the emergence of autoimmune diseases (ADs), and the discovery of PRRs revolutionizing immunology. The second section describes the cGAS-STING signaling pathway mediated cytosolic self-DNA recognition, its evolution, characteristics of self-DNAs activating it, and its role in different inflammatory conditions. The third section describes the role of TLR9 in recognizing self-DNA in the endolysosomes during infections depending on the self-DNA characteristics and various inflammatory diseases. The fourth section discusses about AIM2 (an ALR), which also binds cytosolic self-DNA (with 80–300 base pairs or bp) that inhibits cGAS-STING-dependent type 1 IFN generation but induces inflammation and pyroptosis during different inflammatory conditions. Hence, this trinity of PRRs has evolved to recognize self-DNA as a potential DAMP and comes into action to guard the cellular galaxy. However, their dysregulation proves dangerous to the host and leads to several inflammatory conditions, including sterile-inflammatory conditions autoinflammatory and ADs.

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“…Type I IFNs are secreted cytokines that signal via JAK-STAT signaling to induce transcription of hundreds of anti-viral genes known as interferon-stimulated genes (ISGs) (13,14). STING also activates NF-κB, MAP kinase (15), STAT6 (16), and autophagy-like pathways (17)(18)(19)(20), as well as senescence (21) and cell death (22)(23)(24)(25)(26), although the mechanism of activation of these pathways, and their importance during infection, are less well understood.…”

Section: Introductionmentioning

confidence: 99%

The cyclic dinucleotide 2’3’-cGAMP induces a broad anti-bacterial and anti-viral response in the sea anemone Nematostella vectensis

Margolis¹,

Dietzen²,

Hayes³

et al. 2021

Preprint

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In mammals, the cGAS-cGAMP-STING pathway is crucial for sensing viral infection and initiating an anti-viral type I interferon response. cGAS and STING are highly conserved genes that originated in bacteria and are present in most animals. By contrast, interferons only emerged in vertebrates; thus, the function of STING in invertebrates is unclear. Here, we use the STING ligand 2′3′-cGAMP to activate immune responses in a model cnidarian invertebrate, the starlet sea anemone Nematostella vectensis. Using RNA-Seq, we found that 2′3′-cGAMP induces robust transcription of both anti-viral and anti-bacterial genes, including the conserved transcription factor NF-κB. Knockdown experiments identified a role for NF-κB in specifically inducing anti-bacterial genes downstream of 2′3′-cGAMP, and some of these genes were also found to be induced during Pseudomonas aeruginosa infection. Furthermore, we characterized the protein product of one of the putative anti-bacterial genes, the N. vectensis homolog of Dae4, and found that it has conserved anti-bacterial activity. This work describes an unexpected role of a cGAMP sensing pathway in anti-bacterial immunity and suggests that a broad transcriptional response is an evolutionarily ancestral output of 2′3′-cGAMP signaling in animals.

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STING induces LC3B lipidation onto single-membrane vesicles via the V-ATPase and ATG16L1-WD40 domain

Cited by 117 publications

References 63 publications

ATG16L1 functions in cell homeostasis beyond autophagy

ATG16L1 functions in cell homeostasis beyond autophagy

The Trinity of cGAS, TLR9, and ALRs Guardians of the Cellular Galaxy Against Host-Derived Self-DNA

The cyclic dinucleotide 2’3’-cGAMP induces a broad anti-bacterial and anti-viral response in the sea anemone Nematostella vectensis

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