Structure of Human ATG9A, the Only Transmembrane Protein of the Core Autophagy Machinery

Guardia, Carlos M.; Tan, Xiao-Feng; Lian, Tengfei; Rana, Mitra S.; Zhou, Wenchang; Christenson, Eric T.; Lowry, Augustus J.; Faraldo‐Gómez, José D.; Bonifacino, Juan S.; Jiang, Junchen; Banerjee, Anirban

doi:10.1016/j.celrep.2020.107837

Cited by 135 publications

(150 citation statements)

References 39 publications

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“…In contrast, a recent study showed that Optineurin can directly associate with ATG9A to induce mitophagy without the engagement of FIP200 56 . To validate the direct interaction between Optineurin and ATG9A, we constructed an ATG9A(595-839) fragment that includes the entire C-terminal cytosolic tail of ATG9A based on the recently determined human ATG9A structure 57,58 . Using purified ATG9A(595-839) and full-length Optineurin proteins, our biochemical assays clearly demonstrated that there is no direct interaction between the cytosolic tail of ATG9A and Optineurin in vitro ( Supplementary Fig.…”

Section: Discussionmentioning

confidence: 99%

Phosphorylation regulates the binding of autophagy receptors to FIP200 Claw domain for selective autophagy initiation

Zhou

Liu

et al. 2021

Nat Commun

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The ULK complex initiates the autophagosome formation, and has recently been implicated in selective autophagy by interacting with autophagy receptors through its FIP200 subunit. However, the structural mechanism underlying the interactions of autophagy receptors with FIP200 and the relevant regulatory mechanism remain elusive. Here, we discover that the interactions of FIP200 Claw domain with autophagy receptors CCPG1 and Optineurin can be regulated by the phosphorylation in their respective FIP200-binding regions. We determine the crystal structures of FIP200 Claw in complex with the phosphorylated CCPG1 and Optineurin, and elucidate the detailed molecular mechanism governing the interactions of FIP200 Claw with CCPG1 and Optineurin as well as their potential regulations by kinase-mediated phosphorylation. In addition, we define the consensus FIP200 Claw-binding motif, and find other autophagy receptors that contain this motif within their conventional LC3-interacting regions. In all, our findings uncover a general and phosphoregulatable binding mode shared by many autophagy receptors to interact with FIP200 Claw for autophagosome biogenesis, and are valuable for further understanding the molecular mechanism of selective autophagy.

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Section: Discussionmentioning

confidence: 99%

Phosphorylation regulates the binding of autophagy receptors to FIP200 Claw domain for selective autophagy initiation

Zhou

Liu

et al. 2021

Nat Commun

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“…Current evidence supports a role for AP-4 in promoting autophagosome biogenesis through regulation of autophagy-related protein 9 (ATG9) export from the trans-golgi network to autophagosomes [ 15 , 19 , 20 , 21 ]. ATG9 is the only transmembrane protein of the core autophagy machinery, and its distribution is heavily dependent on vesicular trafficking [ 71 , 72 , 73 ]. Consequently, loss of AP-4 function leads to retention of ATG9 in the trans-golgi network and defective autophagosome generation [ 15 ].…”

Section: Ap-4 Complexmentioning

confidence: 99%

Lysosome Function and Dysfunction in Hereditary Spastic Paraplegias

2021

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Hereditary Spastic Paraplegias (HSPs) are a genetically diverse group of inherited neurological diseases with over 80 associated gene loci. Over the last decade, research into mechanisms underlying HSPs has led to an emerging interest in lysosome dysfunction. In this review, we highlight the different classes of HSPs that have been linked to lysosome defects: (1) a subset of complex HSPs where mutations in lysosomal genes are causally linked to the diseases, (2) other complex HSPs where mutation in genes encoding membrane trafficking adaptors lead to lysosomal defects, and (3) a subset of HSPs where mutations affect genes encoding proteins whose function is primarily linked to a different cellular component or organelle such as microtubule severing and Endoplasmic Reticulum-shaping, while also altering to lysosomes. Interestingly, aberrant axonal lysosomes, associated with the latter two subsets of HSPs, are a key feature observed in other neurodegenerative diseases such as Alzheimer’s disease. We discuss how altered lysosome function and trafficking may be a critical contributor to HSP pathology and highlight the need for examining these features in the cortico-spinal motor neurons of HSP mutant models.

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“…In addition, recent studies have highlighted that TRAPP III-specific proteins (TRAPPC11) are necessary for the close of isolation membranes and recruitment of WIPI4-ATG2 to isolation membranes with the presence of ATG9, perhaps due to its carboxy-terminus, while TRAPPC12 is downstream of TRAPPC11 ( Stanga et al, 2019 ). Interestingly, Guardia et al (2020) have found that ATG9A (human ATG9), a homotrimer with four transmembrane helices, interacts with ATG2 at C-terminal platform domain of ATG9A (1–723 construct and 1-522 construct) to transfer lipids from ATG2 to ATG9A, and then ATG9A can induce the autophagosome membrane curvature for the further processes of autophagy.…”

Section: Overview Of Autophagymentioning

confidence: 99%

The Role of Autophagy in Gastric Cancer Chemoresistance: Friend or Foe?

Tang

et al. 2020

Front. Cell Dev. Biol.

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Gastric cancer is the third most common cause of cancer-related death worldwide. Drug resistance is the main inevitable and vital factor leading to a low 5-year survival rate for patients with gastric cancer. Autophagy, as a highly conserved homeostatic pathway, is mainly regulated by different proteins and non-coding RNAs (ncRNAs) and plays dual roles in drug resistance of gastric cancer. Thus, targeting key regulatory nodes in the process of autophagy by small molecule inhibitors or activators has become one of the most promising strategies for the treatment of gastric cancer in recent years. In this review, we provide a systematic summary focusing on the relationship between autophagy and chemotherapy resistance in gastric cancer. We comprehensively discuss the roles and molecular mechanisms of multiple proteins and the emerging ncRNAs including miRNAs and lncRNAs in the regulation of autophagy pathways and gastric cancer chemoresistance. We also summarize the regulatory effects of autophagy inhibitor and activators on gastric cancer chemoresistance. Understanding the vital roles of autophagy in gastric cancer chemoresistance will provide novel opportunities to develop promising therapeutic strategies for gastric cancer.

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Structure of Human ATG9A, the Only Transmembrane Protein of the Core Autophagy Machinery

Abstract: Highlights d The transmembrane autophagy protein ATG9A is a domainswapped homotrimer d Each ATG9A protomer comprises four transmembrane domains d The ATG9A homotrimer exhibits an internal network of branched cavities d Molecular dynamics simulations show that ATG9A trimers deform membranes

Cited by 135 publications

References 39 publications

Phosphorylation regulates the binding of autophagy receptors to FIP200 Claw domain for selective autophagy initiation

Phosphorylation regulates the binding of autophagy receptors to FIP200 Claw domain for selective autophagy initiation

Lysosome Function and Dysfunction in Hereditary Spastic Paraplegias

The Role of Autophagy in Gastric Cancer Chemoresistance: Friend or Foe?

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