S-acylation of p62 promotes p62 droplet recruitment into autophagosomes in mammalian autophagy
- PMID: 37802024
- PMCID: PMC10552648
- DOI: 10.1016/j.molcel.2023.09.004
S-acylation of p62 promotes p62 droplet recruitment into autophagosomes in mammalian autophagy
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.
Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.
Conflict of interest statement
Declaration of interests E.W.T. is a founder and shareholder in Myricx Pharma Ltd. and receives consultancy or research funding from Kura Oncology, Pfizer Ltd., Samsara Therapeutics, Myricx Pharma Ltd., MSD, Exscientia, and Daiichi Sankyo.
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