气候变化领域集成服务门户(CCPortal): Snx14 proximity labeling reveals a role in saturated fatty acid metabolism and ER homeostasis defective in SCAR20 disease

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DOI	10.1073/PNAS.2011124117
	Snx14 proximity labeling reveals a role in saturated fatty acid metabolism and ER homeostasis defective in SCAR20 disease
	Datta S.; Bowerman J.; Hariri H.; Ugrankar R.; Eckert K.M.; Corley C.; Vale G.; McDonald J.G.; Mike Henne W.
发表日期	2021
ISSN	00278424
起始页码	33282
结束页码	33294
卷号	117 期号:52
英文摘要	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. © 2020 National Academy of Sciences. All rights reserved.
英文关键词	Desaturase; Fatty acid (FA); Lipid droplet (LD); SCAR20 disease; Sorting nexin 14
语种	英语
scopus关键词	acyl coenzyme A desaturase; membrane protein; palmitic acid; protein SCD1; protein Snx14; synexin; unclassified drug; Article; cell death; cell membrane; controlled study; endoplasmic reticulum; enzyme activity; fatty acid metabolism; human; human cell; lipid fingerprinting; lipotoxicity; neuropathology; priority journal; protein analysis; protein expression; protein protein interaction; spinocerebellar degeneration
来源期刊	Proceedings of the National Academy of Sciences of the United States of America
文献类型	期刊论文
条目标识符	http://gcip.llas.ac.cn/handle/2XKMVOVA/179607
作者单位	Department of Cell Biology, UT Southwestern Medical Center, Dallas, TX 75390, United States; Department of Molecular Genetics, UT Southwestern Medical Center, Dallas, TX 75390, United States
推荐引用方式 GB/T 7714	Datta S.,Bowerman J.,Hariri H.,et al. Snx14 proximity labeling reveals a role in saturated fatty acid metabolism and ER homeostasis defective in SCAR20 disease[J],2021,117(52).
APA	Datta S..,Bowerman J..,Hariri H..,Ugrankar R..,Eckert K.M..,...&Mike Henne W..(2021).Snx14 proximity labeling reveals a role in saturated fatty acid metabolism and ER homeostasis defective in SCAR20 disease.Proceedings of the National Academy of Sciences of the United States of America,117(52).
MLA	Datta S.,et al."Snx14 proximity labeling reveals a role in saturated fatty acid metabolism and ER homeostasis defective in SCAR20 disease".Proceedings of the National Academy of Sciences of the United States of America 117.52(2021).