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 Corley, Gonçalo Vale, Jeffrey G. McDonald, W. Mike Henne

Research output: Contribution to journalArticlepeer-review

Abstract

Fatty acids (FAs) are central cellular metabolites that contribute to lipid synthesis, and can be stored or harvested for metabolic energy. Dysregulation in FA processing and storage causes toxic FA accumulation or altered membrane compositions and contributes to metabolic and neurological disorders. Saturated lipids are particularly detrimental to cells, but how lipid saturation levels are maintained remains poorly understood. Here, we identify the cerebellar ataxia spinocerebellar ataxia, autosomal recessive 20 (SCAR20)-associated protein Snx14, an endoplasmic reticulum (ER)–lipid droplet (LD) tethering protein, as a factor required to maintain the lipid saturation balance of cell membranes. We show that following saturated FA (SFA) treatment, the ER integrity of SNX14KO cells is compromised, and both SNX14KO cells and SCAR20 disease patient-derived cells are hypersensitive to SFA-mediated lipotoxic cell death. Using APEX2-based proximity labeling, we reveal the protein composition of Snx14-associated ER–LD contacts and define a functional interaction between Snx14 and Δ-9 FA desaturase SCD1. Lipidomic profiling reveals that SNX14KO cells increase membrane lipid saturation following exposure to palmitate, phenocopying cells with perturbed SCD1 activity. In line with this, SNX14KO cells manifest delayed FA processing and lipotoxicity, which can be rescued by SCD1 overexpression. Altogether, these mechanistic insights reveal a role for Snx14 in FA and ER homeostasis, defects in which may underlie the neuropathology of SCAR20.

Original languageEnglish (US)
Pages (from-to)33282-33294
Number of pages13
JournalProceedings of the National Academy of Sciences of the United States of America
Volume117
Issue number52
DOIs
StatePublished - Dec 2020

Keywords

  • Desaturase
  • Fatty acid (FA)
  • Lipid droplet (LD)
  • SCAR20 disease
  • Sorting nexin 14

ASJC Scopus subject areas

  • General

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