2. Academic Validation
  3. S-acylation of p62 promotes p62 droplet recruitment into autophagosomes in mammalian autophagy

S-acylation of p62 promotes p62 droplet recruitment into autophagosomes in mammalian autophagy

  • Mol Cell. 2023 Oct 5;83(19):3485-3501.e11. doi: 10.1016/j.molcel.2023.09.004.
Xue Huang 1,  Jia Yao 1,  Lu Liu 1,  Jing Chen 1,  Ligang Mei 1,  Jingjing Huangfu 2,  Dong Luo 3,  Xinyi Wang 4,  Changhai Lin 5,  Xiaorong Chen 1,  Yi Yang 1,  Sheng Ouyang 1,  Fujing Wei 1,  Zhuolin Wang 1,  Shaolin Zhang 3,  Tingxiu Xiang 6,  Dante Neculai 7,  Qiming Sun 4,  Eryan Kong 2,  Edward W Tate 8,  Aimin Yang 9
Affiliations

Affiliations

  • 1 School of Life Sciences, Chongqing University, Chongqing 401331, China.
  • 2 Institute of Psychiatry and Neuroscience, Xinxiang Key Laboratory of Protein Palmitoylation and Major Human Diseases, Xinxiang Medical University, Xinxiang, China.
  • 3 School of Pharmacy, Chongqing University, Chongqing 401331, China.
  • 4 International Institutes of Medicine, The Fourth Affiliated Hospital of Zhejiang University School of Medicine, Yiwu, Zhejiang, China; Department of Biochemistry and Department of Cardiology of Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310058, China.
  • 5 School of Life Sciences, Chongqing University, Chongqing 401331, China; Chongqing Key Laboratory of Translational Research for Cancer Metastasis and Individualized Treatment, Chongqing University Cancer Hospital, Chongqing 400030, China.
  • 6 Chongqing Key Laboratory of Translational Research for Cancer Metastasis and Individualized Treatment, Chongqing University Cancer Hospital, Chongqing 400030, China.
  • 7 International Institutes of Medicine, The Fourth Affiliated Hospital of Zhejiang University School of Medicine, Yiwu, Zhejiang, China.
  • 8 Department of Chemistry, Imperial College London, 82 Wood Lane, London W12 0BZ, UK.
  • 9 School of Life Sciences, Chongqing University, Chongqing 401331, China. Electronic address: aimin.yang@cqu.edu.cn.
PMID: 37802024 DOI: 10.1016/j.molcel.2023.09.004
Abstract

p62 is a well-characterized Autophagy receptor that recognizes and sequesters specific cargoes into autophagosomes for degradation. p62 promotes the assembly and removal of ubiquitinated proteins by forming p62-liquid droplets. However, it remains unclear how autophagosomes efficiently sequester p62 droplets. Herein, we report that p62 undergoes reversible S-acylation in multiple human-, rat-, and mouse-derived cell lines, catalyzed by zinc-finger Asp-His-His-Cys S-acyltransferase 19 (ZDHHC19) and deacylated by acyl protein thioesterase 1 (APT1). S-acylation of p62 enhances the affinity of p62 for microtubule-associated protein 1 light chain 3 (LC3)-positive membranes and promotes autophagic membrane localization of p62 droplets, thereby leading to the production of small LC3-positive p62 droplets and efficient autophagic degradation of p62-cargo complexes. Specifically, increasing p62 acylation by upregulating ZDHHC19 or by genetic knockout of APT1 accelerates p62 degradation and p62-mediated autophagic clearance of ubiquitinated proteins. Thus, the protein S-acylation-deacylation cycle regulates p62 droplet recruitment to the autophagic membrane and selective autophagic flux, thereby contributing to the control of selective autophagic clearance of ubiquitinated proteins.

Keywords

APT1; S-acylation; ZDHHC19; autophagy; autophagy receptor; liquid-liquid phase separation; p62 droplet; p62 protein; protein posttranslational modification; selective autophagy.

Figures