Cerebellar ataxia disease–associated Snx14 promotes lipid droplet growth at ER–droplet contacts

Author:

Datta Sanchari1ORCID,Liu Yang1,Hariri Hanaa1ORCID,Bowerman Jade1,Henne W. Mike1ORCID

Affiliation:

1. Department of Cell Biology, University of Texas Southwestern Medical Center, Dallas, TX

Abstract

Lipid droplets (LDs) are nutrient reservoirs used by cells to maintain homeostasis. Nascent droplets form on the endoplasmic reticulum (ER) and grow following an influx of exogenous fatty acids (FAs). The budding of LDs requires extensive ER–LD crosstalk, but how this is regulated remains poorly understood. Here, we show that sorting nexin protein Snx14, an ER-resident protein associated with the cerebellar ataxia SCAR20, localizes to ER–LD contacts following FA treatment, where it promotes LD maturation. Using proximity-based APEX technology and topological dissection, we show that Snx14 accumulates specifically at ER–LD contacts independently of Seipin, where it remains ER-anchored and binds LDs in trans. SNX14KO cells exhibit perturbed LD morphology, whereas Snx14 overexpression promotes LD biogenesis and extends ER–LD contacts. Multi–time point imaging reveals that Snx14 is recruited to ER microdomains containing the fatty acyl-CoA ligase ACSL3, where nascent LDs bud. We propose that Snx14 is a novel marker for ER–LD contacts and regulates FA-stimulated LD growth.

Funder

Welch Foundation

Searle Foundation

National Institutes of Health

National Institute of General Medical Sciences

University of Texas Southwestern

Publisher

Rockefeller University Press

Subject

Cell Biology

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