The lysosomal transporter MFSD1 is essential for liver homeostasis and critically depends on its accessory subunit GLMP
The lysosomal transporter MFSD1 is essential for liver homeostasis and critically depends on its accessory subunit GLMP
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DOI：
10.7554/elife.50025
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发表时间：
2019-10-29
期刊：
影响因子：
7.7
通讯作者：
Damme, Markus
中科院分区：
文献类型：
--
作者：
Lopez, David Massa;Thelen, Melanie;Damme, Markus
溶酶体是细胞内酸性水解酶介导的蛋白水解和细胞降解的主要场所。低分子量分解代谢终产物的输出由介导次级主动或被动转运的多位跨膜蛋白促进。然而，这些溶酶体转运蛋白中的一些仍然是谜。我们提出了一个详细的分析MFSD 1，迄今为止未表征的主要促进超家族的溶酶体家族成员。MFSD 1不是N-糖基化的。它包含转运到溶酶体所需的基于二亮氨酸的分选基序。mfsd 1基因敲除小鼠出现脾肿大和严重的肝脏疾病。从Mfsd 1基因敲除小鼠分离的溶酶体的蛋白质组学揭示GLMP作为MFSD 1的关键辅助亚基。MFSD 1和GLMP物理相互作用。GLMP对于维持溶酶体中MFSD 1的正常水平至关重要，反之亦然。Glmp敲除小鼠模拟Mfsd 1敲除小鼠的表型。我们的数据揭示了一个紧密相连的MFSD 1/GLMP溶酶体膜蛋白转运蛋白复合体。
Lysosomes are major sites for intracellular, acidic hydrolase-mediated proteolysis and cellular degradation. The export of low-molecular-weight catabolic end-products is facilitated by polytopic transmembrane proteins mediating secondary active or passive transport. A number of these lysosomal transporters, however, remain enigmatic. We present a detailed analysis of MFSD1, a hitherto uncharacterized lysosomal family member of the major facilitator superfamily. MFSD1 is not N-glycosylated. It contains a dileucine-based sorting motif needed for its transport to lysosomes. Mfsd1 knockout mice develop splenomegaly and severe liver disease. Proteomics of isolated lysosomes from Mfsd1 knockout mice revealed GLMP as a critical accessory subunit for MFSD1. MFSD1 and GLMP physically interact. GLMP is essential for the maintenance of normal levels of MFSD1 in lysosomes and vice versa. Glmp knockout mice mimic the phenotype of Mfsd1 knockout mice. Our data reveal a tightly linked MFSD1/GLMP lysosomal membrane protein transporter complex.