Snx14 proximity labeling reveals a role in saturated fatty acid metabolism and ER homeostasis defective in SCAR20 disease
Sanchari Datta, Jade Bowerman, Hanaa Hariri, Rupali Ugrankar, Kaitlyn M. Eckert, Chase D. Corley, Gonçalo Vale, Jeffrey G. McDonald, W. Mike Henne
Abstract
Significance SCAR20 disease is an autosomal-recessive spinocerebellar ataxia primarily affecting children, and results from loss-of-function mutations in the SNX14 gene. Snx14 is an endoplasmic reticulum (ER)-localized protein that localizes to ER–lipid droplet (LD) contacts and promotes LD biogenesis following exogenous fatty acid (FA) treatment. Why Snx14 loss causes SCAR20 is unclear. Here, we demonstrate that, following exposure to saturated FAs, Snx14-deficient cells have defective ER homeostasis and altered lipid saturation profiles. We reveal a functional interaction between Snx14 and FA desaturase SCD1. Lipidomics shows Snx14-deficient cells contain elevated saturated lipids, closely mirroring SCD1-defective cells. Furthermore, SCD1 overexpression can rescue Snx14 loss. We propose that Snx14 maintains cellular lipid homeostasis, the loss of which underlies the cellular basis for SCAR20 disease.