S-palmitoylation coordinates the trafficking of ATG9A to mediate autophagy initiation.

Autophagy Pub Date : 2025-05-31 DOI:10.1080/15548627.2025.2509376

Fan Xia, Weining Li, Wenru Wang, Jiru Liu, Xiaolin Li, Jing Cai, Hao Shan, Zhe Cai, Jun Cui

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Abstract

Abbreviation: 17-ODYA: 17-octadecynoic acid; 293T: HEK293T; 2-BP: 2-bromopalmitate; 2CS: Cys155Ser and Cys156Ser; ABE: acyl-biotin exchange; AP: adaptor protein; APEX2: ascorbate peroxidase 2; ATG: autophagy related; baf A₁: bafilomycin A₁; CRISPR: clustered regularly interspaced short palindromic repeats; CTD: C-terminal domain; Cys: cysteine; DAB: 3,3'-diaminobenzidine; EV: empty vector; H₂O₂: hydrogen peroxide; IF: immunofluorescence; IP: immunoprecipitation; KO: knockout; MAP1LC3B/LC3B: microtubule associated protein 1 light chain 3 beta; MTOR: mechanistic target of rapamycin kinase; NTD: N-terminal domain; PAS: phagophore assembly site; PBS: phosphate-buffered saline; PtdIns3K-CI: class III phosphatidylinositol 3-kinase complex I; PM: plasma membrane; PTM: post-translational modifications; Ser: serine; siRNA: small interfering RNA; SQSTM1/p62: sequestosome 1; TEM: transmission electron microscopy; TGN: trans-Golgi network; ULK1: unc-51 like autophagy activating kinase 1; WCL, whole cell lysates; WDR45/WIPI4: WD repeat domain 45; WT: wild-type; ZFYVE1/DFCP1: zinc finger FYVE-type containing 1.

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s -棕榈酰化协调转运ATG9A介导自噬起始。

巨噬（Macroautophagy，以下简称自噬）是一种主要的细胞内分解代谢过程，从酵母到哺乳动物在进化上都是保守的，并且与广泛的人类疾病有关。自噬的形态学特征是双膜自噬体的形成。ATG9A是一种多跨膜蛋白和脂质超燃酶，是自噬机制的核心组成部分，补充膜源并平衡跨膜双层的脂质。在这里，我们报道棕榈酰转移酶ZDHHC5对于自噬体成核和随后的自噬体形成是必不可少的。自噬诱导后，ZDHHC5通过网格蛋白介导的内吞作用从质膜内化到细胞内。该酶激活ATG9A在半胱氨酸155/156处的s-棕榈酰化，协调ATG9A与异四聚体衔接蛋白复合体家族成员AP4E1/AP-4ε的相互作用，并随后从反式高尔基网络运输到内体室。功能上，ATG9A s -棕榈酰化损伤导致自噬起始和自噬体形成缺陷。这些发现确定了一种调节机制，通过ZDHHC5介导ATG9A s -棕榈酰化，协调ATG9A与AP4E1的结合和囊泡运输事件，从而确保膜运输的时空保真度和自噬稳态的维持。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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Autophagy

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