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.
- 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: [email protected].
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.