Snx14 proximity labeling reveals a role in saturated fatty acid metabolism and ER homeostasis defective in SCAR20 disease

Datta Sanchari; Bowerman Jade; Hariri HanaaUgrankar RupaliEckert Kaitlyn M.Corley ChaseVale GoncaloMcDonald Jeffrey G.Henne W. Mike

首页> 外文期刊>Proceedings of the National Academy of Sciences of the United States of America. >Snx14 proximity labeling reveals a role in saturated fatty acid metabolism and ER homeostasis defective in SCAR20 disease

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Snx14 proximity labeling reveals a role in saturated fatty acid metabolism and ER homeostasis defective in SCAR20 disease

机译：Snx14 proximity labeling reveals a role in saturated fatty acid metabolism and ER homeostasis defective in SCAR20 disease

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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 SNX14(KO) cells is compromised, and both SNX14(KO) 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 Delta-9 FA desaturase SCD1. Lipidomic profiling reveals that SNX14(KO) cells increase membrane lipid saturation following exposure to palmitate, phenocopying cells with perturbed SCD1 activity. In line with this, SNX14(KO) 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.

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《Proceedings of the National Academy of Sciences of the United States of America.》 |2020年第52期|33282-33294|共13页
作者
Datta Sanchari; Bowerman Jade; Hariri HanaaUgrankar RupaliEckert Kaitlyn M.Corley ChaseVale GoncaloMcDonald Jeffrey G.Henne W. Mike;
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作者单位

Dept Mol Genet,UT Southwestern Med Ctr;

Dept Cell Biol,UT Southwestern Med Ctr;

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收录信息美国《科学引文索引》(SCI);美国《生物学医学文摘》(MEDLINE);美国《化学文摘》(CA);
原文格式 PDF
正文语种英语
中图分类自然科学总论;
关键词
fatty acid (FA); desaturase; sorting nexin 14; SCAR20 disease; lipid droplet (LD); LIPOTOXICITY; DISRUPTION; DYSFUNCTION; MUTATIONS; PROTEINS; DYNAMICS; ENZYMES; ATAXIA; CELLS; GENE;

Snx14 proximity labeling reveals a role in saturated fatty acid metabolism and ER homeostasis defective in SCAR20 disease

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