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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, View ORCID ProfileMike Henne
doi: https://doi.org/10.1101/2020.05.31.126441
Sanchari Datta
1Department of Cell Biology, UT Southwestern Medical Center, 6000 Harry Hines Blvd, Dallas, TX 75390
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Jade Bowerman
1Department of Cell Biology, UT Southwestern Medical Center, 6000 Harry Hines Blvd, Dallas, TX 75390
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Hanaa Hariri
1Department of Cell Biology, UT Southwestern Medical Center, 6000 Harry Hines Blvd, Dallas, TX 75390
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Rupali Ugrankar
1Department of Cell Biology, UT Southwestern Medical Center, 6000 Harry Hines Blvd, Dallas, TX 75390
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Kaitlyn M. Eckert
2Department of Molecular Genetics, UT Southwestern Medical Center, 6000 Harry Hines Blvd, Dallas, TX 75390
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Chase Corley
2Department of Molecular Genetics, UT Southwestern Medical Center, 6000 Harry Hines Blvd, Dallas, TX 75390
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Gonçalo Vale
2Department of Molecular Genetics, UT Southwestern Medical Center, 6000 Harry Hines Blvd, Dallas, TX 75390
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Jeffrey G. McDonald
2Department of Molecular Genetics, UT Southwestern Medical Center, 6000 Harry Hines Blvd, Dallas, TX 75390
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Mike Henne
1Department of Cell Biology, UT Southwestern Medical Center, 6000 Harry Hines Blvd, Dallas, TX 75390
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  • ORCID record for Mike Henne
  • For correspondence: mike.henne@utsouthwestern.edu
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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 SCAR20-associated protein Snx14, an endoplasmic reticulum (ER)-lipid droplet (LD) tethering protein, as a novel factor required to maintain the lipid saturation balance of cell membranes. We show that SNX14KO cells and SCAR20 disease patient-derived cells are hypersensitive to saturated FA (SFA)-mediated lipotoxic cell death that compromises ER integrity. 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 reduced SCD1 activity. In line with this, SNX14KO cells manifest delayed FA processing and lipotoxicity, which can be rescued by SCD1 over-expression. Altogether these mechanistic insights reveal a role for Snx14 in FA and ER homeostasis, defects in which may underlie the neuropathology of SCAR20.

Significance Statement 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 FA treatment, but why Snx14 loss causes SCAR20 is unclear. Here, we demonstrate that following exposure to saturated fatty acids, Snx14-deficient cells have defective ER homeostasis and altered lipid saturation profiles. We reveal a functional interaction between Snx14 and fatty acid (FA) desaturase SCD1. Lipidomics shows Snx14-deficient cells contain elevated saturated lipids, closely mirroring SCD1-defective cells. Furthermore, SCD1 over-expression can rescue Snx14 loss. We propose that Snx14 maintains cellular lipid homeostasis, the loss of which underlies the cellular basis for SCAR20 disease.

Competing Interest Statement

The authors have declared no competing interest.

Footnotes

  • 1) new experiments dissecting how Snx14 loss impacts SCD1 activity in vitro 2) further analysis/dissection of Snx14-APEX2 interactome 3) further control experiments examining impact of Snx14 loss on cellular fatty acid uptake 4) new experiments examining impact of Snx14 loss on UPR signaling and caspase-mediated cell death

Copyright 
The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. All rights reserved. No reuse allowed without permission.
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Posted October 01, 2020.
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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, Mike Henne
bioRxiv 2020.05.31.126441; doi: https://doi.org/10.1101/2020.05.31.126441
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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, Mike Henne
bioRxiv 2020.05.31.126441; doi: https://doi.org/10.1101/2020.05.31.126441

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