VPS4A is the selective receptor for lipophagy in mice and humans

Debajyoti Das; Mridul Sharma; Deepanshi Gahlot; Shervin S Nia; Chandrima Gain; Matthew Mecklenburg; Z Hong Zhou; Mathieu Bourdenx; Lipi Thukral; Nuria Martinez-Lopez; Rajat Singh

doi:10.1016/j.molcel.2024.10.022

VPS4A is the selective receptor for lipophagy in mice and humans

Mol Cell. 2024 Nov 21;84(22):4436-4453.e8. doi: 10.1016/j.molcel.2024.10.022. Epub 2024 Nov 8.

Authors

Affiliations

¹ Department of Medicine, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA, USA; Division of Digestive Diseases, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA, USA.
² CSIR-Institute of Genomics and Integrative Biology, New Delhi, India; Academy of Scientific and Innovative Research, Ghaziabad, India.
³ California NanoSystems Institute, University of California, Los Angeles, Los Angeles, CA, USA; Department of Chemistry and Biochemistry, University of California, Los Angeles, Los Angeles, CA, USA; Department of Microbiology, Immunology and Molecular Genetics, University of California, Los Angeles, Los Angeles, CA, USA.
⁴ California NanoSystems Institute, University of California, Los Angeles, Los Angeles, CA, USA.
⁵ UK Dementia Research Institute, London, UK; UCL Queen Square Institute of Neurology, London, UK.
⁶ Department of Medicine, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA, USA; Division of Digestive Diseases, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA, USA; Comprehensive Liver Research Center at University of California, Los Angeles, Los Angeles, CA, USA.
⁷ Department of Medicine, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA, USA; Division of Digestive Diseases, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA, USA; Comprehensive Liver Research Center at University of California, Los Angeles, Los Angeles, CA, USA. Electronic address: rajatsingh@mednet.ucla.edu.

PMID: 39520981
PMCID: PMC11631789 (available on 2025-11-21)
DOI: 10.1016/j.molcel.2024.10.022

Abstract

Lipophagy is a ubiquitous mechanism for degradation of lipid droplets (LDs) in lysosomes. Autophagy receptors selectively target organelles for lysosomal degradation. The selective receptor for lipophagy remains elusive. Using mouse liver phosphoproteomics and human liver transcriptomics, we identify vacuolar-protein-sorting-associated protein 4A (VPS4A), a member of a large family AAA+ ATPases, as a selective receptor for lipophagy. We show that phosphorylation of VPS4A on Ser^95,97 and its localization to LDs in response to fasting drives lipophagy. Imaging/three-dimensional (3D) reconstruction and biochemical analyses reveal the concomitant degradation of VPS4A and LDs in lysosomes in an autophagy-gene-7-sensitive manner. Either silencing VPS4A or targeting VPS4A^S95,S97 phosphorylation or VPS4A binding to LDs or LC3 blocks lipophagy without affecting other forms of selective autophagy. Finally, VPS4A levels and markers of lipophagy are markedly reduced in human steatotic livers-revealing a fundamental role of VPS4A as the lipophagy receptor in mice and humans.

Keywords: MASLD; VPS4A; autophagy; human; lipid droplet; lipophagy; liver; lysosome; phosphorylation; receptor.

MeSH terms

ATPases Associated with Diverse Cellular Activities* / genetics
ATPases Associated with Diverse Cellular Activities* / metabolism
Animals
Autophagy*
Endosomal Sorting Complexes Required for Transport
Fatty Liver* / genetics
Fatty Liver* / metabolism
Fatty Liver* / pathology
Humans
Lipid Droplets / metabolism
Liver* / metabolism
Lysosomes / genetics
Lysosomes / metabolism
Male
Mice
Mice, Inbred C57BL
Microtubule-Associated Proteins / genetics
Microtubule-Associated Proteins / metabolism
Phosphorylation
Vacuolar Proton-Translocating ATPases

Substances

ATPases Associated with Diverse Cellular Activities
VPS4A protein, human
Microtubule-Associated Proteins
Vacuolar Proton-Translocating ATPases
Endosomal Sorting Complexes Required for Transport

Abstract

MeSH terms

Substances

Grants and funding