Members of the autophagy class III phosphatidylinositol 3-kinase complex I interact with GABARAP and GABARAPL1 via LIR motifs

Birgisdottir, Åsa Birna; Mouilleron, S.; Bhujabal, Zambarlal; Wirth, Martina; Sjøttem, Eva; Evjen, Gry; Zhang, Wenxin; Lee, Rebecca; O’Reilly, Nicola; Tooze, Sharon A.; Lamark, Trond; Johansen, Terje

doi:10.1080/15548627.2019.1581009

Cited by 87 publications

(111 citation statements)

References 70 publications

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“…AIMs were initially identified to be utilized in selective autophagy receptors for interacting with Atg8-family proteins, and later they were also found in core Atg proteins [17][18][19][20][21][22][23][24][25][26][27][28][29][30]54]. The identification of the Atg38 AIM in this study expands the list of AIMs in core Atg proteins, underscoring the ubiquity of the interactions between Atg8 and other core Atg proteins in autophagy.…”

Section: Discussionmentioning

confidence: 68%

Atg38-Atg8 interaction in fission yeast establishes a positive feedback loop to promote autophagy

Sun

Jiang

et al. 2020

Autophagy

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Macroautophagy (autophagy) is driven by the coordinated actions of core autophagy-related (Atg) proteins. Atg8, the core Atg protein generally considered acting most downstream, has recently been shown to interact with other core Atg proteins via their Atg8-family-interacting motifs (AIMs). However, the extent, functional consequence, and evolutionary conservation of such interactions remain inadequately understood. Here, we show that, in the fission yeast Schizosaccharomyces pombe, Atg38, a subunit of the phosphatidylinositol 3-kinase (PtdIns3K) complex I, interacts with Atg8 via an AIM, which is highly conserved in Atg38 proteins of fission yeast species, but not conserved in Atg38 proteins of other species. This interaction recruits Atg38 to Atg8 on the phagophore assembly site (PAS) and consequently enhances PAS accumulation of the PtdIns3K complex I and Atg proteins acting downstream of the PtdIns3K complex I, including Atg8. The disruption of the Atg38-Atg8 interaction leads to the reduction of autophagosome size and autophagic flux. Remarkably, the loss of this interaction can be compensated by an artificial Atg14-Atg8 interaction. Our findings demonstrate that the Atg38-Atg8 interaction in fission yeast establishes a positive feedback loop between Atg8 and the PtdIns3K complex I to promote efficient autophagosome formation, underscore the prevalence and diversity of AIMmediated connections within the autophagic machinery, and reveal unforeseen flexibility of such connections.

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Section: Discussionmentioning

confidence: 68%

Atg38-Atg8 interaction in fission yeast establishes a positive feedback loop to promote autophagy

Sun

Jiang

et al. 2020

Autophagy

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“…This raises an ongoing question as to how specificity within the system is achieved, particularly in mammalian systems that are complicated by the expression of six LC3/GABARAP isoforms. We, and others [13,43,44], have attempted to decipher the code that dictates whether a protein with a particular LIR sequence will preferentially interact with LC3 over GABARAP.…”

Section: Resultsmentioning

confidence: 99%

A conserved ATG2‐GABARAP family interaction is critical for phagophore formation

et al. 2020

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The intracellular trafficking pathway, macroautophagy, is a recycling and disposal service that can be upregulated during periods of stress to maintain cellular homeostasis. An essential phase is the elongation and closure of the phagophore to seal and isolate unwanted cargo prior to lysosomal degradation. Human ATG2A and ATG2B proteins, through their interaction with WIPI proteins, are thought to be key players during phagophore elongation and closure, but little mechanistic detail is known about their function. We have identified a highly conserved motif driving the interaction between human ATG2 and GABARAP proteins that is in close proximity to the ATG2‐WIPI4 interaction site. We show that the ATG2A‐GABARAP interaction mutants are unable to form and close phagophores resulting in blocked autophagy, similar to ATG2A/ATG2B double‐knockout cells. In contrast, the ATG2A‐WIPI4 interaction mutant fully restored phagophore formation and autophagy flux, similar to wild‐type ATG2A. Taken together, we provide new mechanistic insights into the requirements for ATG2 function at the phagophore and suggest that an ATG2‐GABARAP/GABARAP‐L1 interaction is essential for phagophore formation, whereas ATG2‐WIPI4 interaction is dispensable.

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“…Although it is generally accepted that mAtg8s are important for autophagy, and that mAtg8 lipidation and puncta formation herald autophagy induction and isolation membrane formation, the core function of mAtg8s and possibly a direct role in autophagosomal membrane remodeling remains to be defined. Nevertheless, many of the cargos, selective autophagy receptors, and regulatory components (ULK, ATG13, FIP200, ATG14, Beclin 1, VPS34, ATG4) contain LC3-interacting regions (LIRs) and can either recruit cargo (Bjorkoy et al, 2005;Birgisdottir et al, 2013) or organize core autophagy machinery (Alemu et al, 2012;Skytte Rasmussen et al, 2017;Birgisdottir et al, 2019). Nevertheless, many of the cargos, selective autophagy receptors, and regulatory components (ULK, ATG13, FIP200, ATG14, Beclin 1, VPS34, ATG4) contain LC3-interacting regions (LIRs) and can either recruit cargo (Bjorkoy et al, 2005;Birgisdottir et al, 2013) or organize core autophagy machinery (Alemu et al, 2012;Skytte Rasmussen et al, 2017;Birgisdottir et al, 2019).…”

Section: Introductionmentioning

confidence: 99%

Mammalian Atg8 proteins regulate lysosome and autolysosome biogenesis through SNARE s

Abudu

Kumar

et al. 2019

The EMBO Journal

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Mammalian homologs of yeast Atg8 protein (mAtg8s) are important in autophagy, but their exact mode of action remains ill-defined. Syntaxin 17 (Stx17), a SNARE with major roles in autophagy, was recently shown to bind mAtg8s. Here, we identified LC3-interacting regions (LIRs) in several SNAREs that broaden the landscape of the mAtg8-SNARE interactions. We found that Syntaxin 16 (Stx16) and its cognate SNARE partners all have LIR motifs and bind mAtg8s. Knockout of Stx16 caused defects in lysosome biogenesis, whereas a Stx16 and Stx17 double knockout completely blocked autophagic flux and decreased mitophagy, pexophagy, xenophagy, and ribophagy. Mechanistic analyses revealed that mAtg8s and Stx16 control several properties of lysosomal compartments including their function as platforms for active mTOR. These findings reveal a broad direct interaction of mAtg8s with SNAREs with impact on membrane remodeling in eukaryotic cells and expand the roles of mAtg8s to lysosome biogenesis.

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Members of the autophagy class III phosphatidylinositol 3-kinase complex I interact with GABARAP and GABARAPL1 via LIR motifs

Cited by 87 publications

References 70 publications

Atg38-Atg8 interaction in fission yeast establishes a positive feedback loop to promote autophagy

Atg38-Atg8 interaction in fission yeast establishes a positive feedback loop to promote autophagy

A conserved ATG2‐GABARAP family interaction is critical for phagophore formation

Mammalian Atg8 proteins regulate lysosome and autolysosome biogenesis through SNARE s

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