2. Academic Validation
  3. Deacetylation of ATG16L1 is required for LC3-associated lysosomal microautophagy

Deacetylation of ATG16L1 is required for LC3-associated lysosomal microautophagy

  • Autophagy. 2025 Aug 28:1-15. doi: 10.1080/15548627.2025.2551669.
Qian Wang 1,  Wei Wan 2,  Hongtao Zhang 1,  Tianhua Zhou 2,  Han-Ming Shen 3,  Pingtong Huang 4,  Wei Liu 1 4
Affiliations

Affiliations

  • 1 Center for Metabolism Research, International Institutes of Medicine, International School of Medicine and the Fourth Affiliated Hospital of Zhejiang University, Yiwu, China.
  • 2 Department of Biochemistry, and Department of Thoracic Surgery of Sir Run Run Shaw Hospital Zhejiang University School of Medicine, Hangzhou, China.
  • 3 Faculty of Health Sciences, Ministry of Education Frontiers Science Center for Precision Oncology, University of Macau, Macau, China.
  • 4 Department of Ultrasound Medicine and State Key laboratory of Transvascular Implantation Devices, The Second Affiliated Hospital of Zhejiang University School of Medicine, Hangzhou, China.
PMID: 40851277 DOI: 10.1080/15548627.2025.2551669
Abstract

Microautophagy is a selective cellular process in which endolysosomes directly engulf cytoplasmic cargo through membrane invagination. The regulatory mechanisms governing microautophagy remain poorly understood. Here, we identified the deacetylation of ATG16L1 as a critical regulator of LC3-associated lysosomal microautophagy. We demonstrate that ATG16L1 acetylation is dynamically controlled by the acetyltransferase KAT2B and the deacetylase HDAC3. Under lysosomal osmotic stress or glucose deprivation, HDAC3-mediated deacetylation of ATG16L1 within its WD40 domain promotes its interaction with V-ATPase, facilitating ATG16L1 recruitment to lysosomal membranes. While dispensable for macroautophagy, this post-translational modification is essential for LC3 lipidation on lysosomes and enables lysosomal recovery, including the restoration of lysosomal size and degradative capacity following stress. Our results reveal a key role for ATG16L1 deacetylation in driving LC3-associated microautophagy to maintain lysosomal homeostasis.

Keywords

ATG16L1; Acetylation; LC3 lipidation; LC3-associated microautophagy; V-ATPase; lysosome.

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