VPS4A is the Selective Receptor for Lipophagy in Mice and Humans

Overview

Journal Mol Cell

Publisher Cell Press

Specialty Cell Biology

Date 2024 Nov 9

PMID 39520981

Authors

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

Affiliations

Soon will be listed here.

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 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 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.

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