A conserved glycine residue in the C-terminal region of human ATG9A is required for its transport from the endoplasmic reticulum to the Golgi apparatus

Staudt, Catherine; Gilis, Florentine; Tevel, Virginie; Jadot, Michel; Boonen, Marielle

doi:10.1016/j.bbrc.2016.09.097

Cited by 4 publications

(5 citation statements)

References 25 publications

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“…Initial 2-dimensional (2D) classification of the data revealed the presence of monomers, dimers and trimers, consistent with previous findings suggesting that ATG9 self-interacts independent of other autophagy factors (Figure 1C; Fig. S2) [37,38]. ATG9 consists of a highly conserved membrane-bound core region consisting of six transmembrane helices (TM1-6) flanked by intrinsically disordered N-and C-terminal cytoplasmic regions (Fig.…”

Section: Isolation and Characterization Of Arabidopsis Atg9supporting

confidence: 87%

“…Our structural analysis shows that monomers in the plant ATG9 self-interacts similar to its yeast and the human counterparts [37,38]. For yeast Atg9, a self-interaction motif has been identified in the C-terminal region of the protein, consisting of the amino acid residues 766-770, and deletion of this motif has been shown to be sufficient to impair its ability to form oligomers thus acutely blocking autophagy progression [38].…”

Section: Discussionmentioning

confidence: 82%

“…Furthermore, our study revealed that plant ATG9 self-interacts via multiple regions, unlike the yeast counterpart. In humans, since mutations introduced in the C-terminal region also failed to disrupt ATG9 self-interaction [37], it is likely that human ATG9A also trimerizes via multiple interaction interfaces.…”

Section: Discussionmentioning

confidence: 99%

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Subnanometer resolution cryo-EM structure of Arabidopsis thaliana ATG9

Lai

Wong

et al. 2019

Autophagy

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Macroautophagy/autophagy is an essential process for the maintenance of cellular homeostasis by recycling macromolecules under normal and stress conditions. ATG9 (autophagy related 9) is the only integral membrane protein in the autophagy core machinery and has a central role in mediating autophagosome formation. In cells, ATG9 exists on mobile vesicles that traffic to the growing phagophore, providing an essential membrane source for the formation of autophagosomes. Here we report the three-dimensional structure of ATG9 from Arabidopsis thaliana at 7.8 Å resolution, determined by single particle cryo-electron microscopy. ATG9 organizes into a homotrimer, with each protomer contributing at least six transmembrane α-helices. At the center of the trimer, the protomers interact via their membrane-embedded and C-terminal cytoplasmic regions. Combined with prediction of protein contacts using sequence co-evolutionary information, the structure provides molecular insights into the ATG9 architecture and testable hypotheses for the molecular mechanism of autophagy progression regulated by ATG9.

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Section: Isolation and Characterization Of Arabidopsis Atg9supporting

confidence: 87%

Section: Discussionmentioning

confidence: 82%

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Subnanometer resolution cryo-EM structure of Arabidopsis thaliana ATG9

Lai

Wong

et al. 2019

Autophagy

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“…These include several phosphorylations with over 20 independent mass spectrometry identifications (S735, S738, S741, S828) and an AMPK‐mediated phosphorylation at S761 that we identified as a 14‐3‐3ζ docking site (Weerasekara et al , 2014). In addition, there is evidence from structural and molecular studies that ATG9A self‐associates via its C termini, which might further expand its ability to act as a protein docking site or signaling hub (He et al , 2008; Staudt et al , 2016; Lai et al , 2020). In support of this idea, we found that ATG9A fused to split‐mVenus molecules at its C termini produced robust BiFC signal in a perinuclear pattern (Fig EV1B), consistent with known localization patterns of ATG9A (Young et al , 2006; Orsi et al , 2012).…”

Section: Resultsmentioning

confidence: 99%

BioID reveals an ATG9A interaction with ATG13‐ATG101 in the degradation of p62/SQSTM1‐ubiquitin clusters

et al. 2021

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ATG9A, the only multi-pass transmembrane protein among core ATG proteins, is an essential regulator of autophagy, yet its regulatory mechanisms and network of interactions are poorly understood. Through quantitative BioID proteomics, we identify a network of ATG9A interactions that includes members of the ULK1 complex and regulators of membrane fusion and vesicle trafficking, including the TRAPP, EARP, GARP, exocyst, AP-1, and AP-4 complexes. These interactions mark pathways of ATG9A trafficking through ER, Golgi, and endosomal systems. In exploring these data, we find that ATG9A interacts with components of the ULK1 complex, particularly ATG13 and ATG101. Using knockout/reconstitution and split-mVenus approaches to capture the ATG13-ATG101 dimer, we find that ATG9A interacts with ATG13-ATG101 independently of ULK1. Deletion of ATG13 or ATG101 causes a shift in ATG9A distribution, resulting in an aberrant accumulation of ATG9A at stalled clusters of p62/SQSTM1 and ubiquitin, which can be rescued by an ULK1 binding-deficient mutant of ATG13. Together, these data reveal ATG9A interactions in vesicletrafficking and autophagy pathways, including a role for an ULK1independent ATG13 complex in regulating ATG9A.

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“…ATG9A is an integral membrane protein that involves in autophagosome formation 30 . It is found between the phagophore assembly site (PAS)/pre-autophagosomal structure and peripheral sites like the Golgi apparatus 31 – 33 , and essential for autophagy initiation. The mechanisms of ATG9A trafficking remain unclear, although previous reports have revealed that ATG9A has an important effect on autophagosome formation 20 , 21 , 34 .…”

Section: Discussionmentioning

confidence: 99%

Deregulation of ATG9A by impaired AR signaling induces autophagy in prostate stromal fibroblasts and promotes BPH progression

et al. 2018

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The activation of androgen receptor (AR) signaling plays an essential role in both prostate stromal cells and epithelial cells during the development of benign prostatic hyperplasia (BPH). Here we demonstrated that androgen ablation after 5α-reductase inhibitor (5-ARI) treatment induced autophagy in prostate stromal fibroblasts inhibiting cell apoptosis. In addition, we found that ATG9A expression was increased after androgen ablation, which facilitated autophagic flux development. Knockdown of ATG9A not only inhibited autophagy notably in prostate stromal fibroblasts, but also reduced the volumes of prostate stromal fibroblast and epithelial cell recombinant grafts in nude mice. In conclusion, our findings suggested that ATG9A upregulation after long-term 5-ARI treatment constitutes a possible mechanism of BPH progression. Thus, combined treatment with 5-ARI and autophagy inhibitory agents would reduce the risk of BPH progression.

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A conserved glycine residue in the C-terminal region of human ATG9A is required for its transport from the endoplasmic reticulum to the Golgi apparatus

Cited by 4 publications

References 25 publications

Subnanometer resolution cryo-EM structure of Arabidopsis thaliana ATG9

Subnanometer resolution cryo-EM structure of Arabidopsis thaliana ATG9

BioID reveals an ATG9A interaction with ATG13‐ATG101 in the degradation of p62/SQSTM1‐ubiquitin clusters

Deregulation of ATG9A by impaired AR signaling induces autophagy in prostate stromal fibroblasts and promotes BPH progression

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