Spns1 is a lysophospholipid transporter mediating lysosomal phospholipid salvage.
Spns1 is a lysophospholipid transporter mediating lysosomal phospholipid salvage.
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DOI：
10.1073/pnas.2210353119
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发表时间：
2022-10-04
影响因子：
11.1
通讯作者：
中科院分区：
文献类型：
--
作者：
溶酶体介导大分子的水解，分解产物必须被运出，这一过程的失败可能导致溶酶体贮积病。虽然氨基酸、单糖和离子的溶酶体转运体已经被表征，但对脂质转运体的身份知之甚少，特别是溶酶体是否输出溶血磷脂，这是磷脂酰胆碱和磷脂酰乙醇胺的分解产物，这是最丰富的膜磷脂。本研究将基于细胞的筛选与生化、细胞和体内模型相结合，以确定SPNS1，一种以前孤立的转运蛋白，作为转运蛋白，介导溶血磷脂的限速溶酶体外排，使其再循环到细胞磷脂池中。SPNS1的去孤儿化为研究溶脂转运和再循环在生理和疾病中的作用奠定了基础。溶酶体是蛋白质、碳水化合物和脂质降解的核心，并将其回收到细胞质中进行再利用。氨基酸、糖和胆固醇的溶酶体转运体已被确定，这些分子在细胞质中的代谢命运也已被阐明。值得注意的是，目前尚不清楚溶酶体是否存在于细胞膜的主要成分甘油磷脂中。通过对孤儿溶酶体转运蛋白的转运试验筛选，我们确定了主要的促进剂超家族蛋白Spns1，它在所有组织中普遍表达为质子依赖的溶血磷脂酰胆碱（LPC）和溶血磷脂酰乙醇胺（LPE）转运蛋白，LPC和LPE分别是最丰富的真核磷脂，磷脂酰胆碱和磷脂酰乙醇胺的溶酶体分解产物。细胞、斑马鱼胚胎和小鼠肝脏中Spns1的缺乏导致LPC和LPE种的溶酶体积聚，并对溶酶体功能产生病理影响。利用靶向溶酶体的稳定同位素标记的磷脂载脂蛋白E纳米盘通量分析表明，LPC以依赖spns1的方式从溶酶体转运，并重新酯化回到磷脂酰胆碱的细胞质池中。我们的研究结果确定了从溶酶体到细胞质的磷脂回收途径，该途径依赖于Spns1，对维持正常的溶酶体功能至关重要。
Lysosomes mediate the hydrolysis of macromolecules for which the breakdown products must be transported out, failure of which could result in lysosomal storage diseases. While lysosomal transporters for amino acids, monosaccharides, and ions have been characterized, less is known about the identity of lipid transporters, particularly whether lysosomes export lysophospholipids that are breakdown products of phosphatidylcholine and phosphatidylethanolamine, the most abundant membrane phospholipids. This study combined a cell-based screen with biochemical, cell, and in vivo models to identify SPNS1, a previously orphaned transporter, as the transporter that mediates the rate-limiting lysosomal efflux of lysophospholipids for their recycling into cellular phospholipid pools. The deorphanization of SPNS1 sets a foundation for studying the role of lysolipid transport and recycling in physiology and disease. The lysosome is central to the degradation of proteins, carbohydrates, and lipids and their salvage back to the cytosol for reutilization. Lysosomal transporters for amino acids, sugars, and cholesterol have been identified, and the metabolic fates of these molecules in the cytoplasm have been elucidated. Remarkably, it is not known whether lysosomal salvage exists for glycerophospholipids, the major constituents of cellular membranes. By using a transport assay screen against orphan lysosomal transporters, we identified the major facilitator superfamily protein Spns1 that is ubiquitously expressed in all tissues as a proton-dependent lysophosphatidylcholine (LPC) and lysophosphatidylethanolamine (LPE) transporter, with LPC and LPE being the lysosomal breakdown products of the most abundant eukaryotic phospholipids, phosphatidylcholine and phosphatidylethanolamine, respectively. Spns1 deficiency in cells, zebrafish embryos, and mouse liver resulted in lysosomal accumulation of LPC and LPE species with pathological consequences on lysosomal function. Flux analysis using stable isotope-labeled phospholipid apolipoprotein E nanodiscs targeted to lysosomes showed that LPC was transported out of lysosomes in an Spns1-dependent manner and re-esterified back into the cytoplasmic pools of phosphatidylcholine. Our findings identify a phospholipid salvage pathway from lysosomes to the cytosol that is dependent on Spns1 and critical for maintaining normal lysosomal function.
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影响因子：
64.8
作者：
Jumper J;Evans R;Pritzel A;Green T;Figurnov M;Ronneberger O;Tunyasuvunakool K;Bates R;Žídek A;Potapenko A;Bridgland A;Meyer C;Kohl SAA;Ballard AJ;Cowie A;Romera-Paredes B;Nikolov S;Jain R;Adler J;Back T;Petersen S;Reiman D;Clancy E;Zielinski M;Steinegger M;Pacholska M;Berghammer T;Bodenstein S;Silver D;Vinyals O;Senior AW;Kavukcuoglu K;Kohli P;Hassabis D
通讯作者：
Hassabis D
影响因子：
64.8
作者：
Nguyen, Long N.;Ma, Dongliang;Silver, David L.
通讯作者：
Silver, David L.
影响因子：
48
作者：
Gibson, Daniel G.;Young, Lei;Smith, Hamilton O.
通讯作者：
Smith, Hamilton O.
影响因子：
4.8
作者：
Hannah, VC;Ou, JF;Brown, MS
通讯作者：
Brown, MS
影响因子：
5.3
作者：
Hiraoka, Miki;Abe, Akira;Shayman, James A.
通讯作者：
Shayman, James A.