TMEM16K 是一种细胞内体分选的细胞器间调节蛋白。
TMEM16K is an interorganelle regulator of endosomal sorting.
机构信息
Departments of Physiology, Biochemistry and Biophysics, University of California at San Francisco, San Francisco, CA, 94158, USA.
Department of Pharmaceutical Chemistry, University of California San Francisco, San Francisco, CA, 94158, USA.
出版信息
Nat Commun. 2020 Jul 3;11(1):3298. doi: 10.1038/s41467-020-17016-8.
Communication between organelles is essential for their cellular homeostasis. Neurodegeneration reflects the declining ability of neurons to maintain cellular homeostasis over a lifetime, where the endolysosomal pathway plays a prominent role by regulating protein and lipid sorting and degradation. Here we report that TMEM16K, an endoplasmic reticulum lipid scramblase causative for spinocerebellar ataxia (SCAR10), is an interorganelle regulator of the endolysosomal pathway. We identify endosomal transport as a major functional cluster of TMEM16K in proximity biotinylation proteomics analyses. TMEM16K forms contact sites with endosomes, reconstituting split-GFP with the small GTPase RAB7. Our study further implicates TMEM16K lipid scrambling activity in endosomal sorting at these sites. Loss of TMEM16K function led to impaired endosomal retrograde transport and neuromuscular function, one of the symptoms of SCAR10. Thus, TMEM16K-containing ER-endosome contact sites represent clinically relevant platforms for regulating endosomal sorting.
细胞器之间的通讯对于它们的细胞内稳态至关重要。神经退行性变反映了神经元在其一生中维持细胞内稳态的能力下降，其中内溶酶体途径通过调节蛋白质和脂质的分拣和降解起着突出作用。在这里，我们报告称，导致脊髓小脑共济失调（SCAR10）的内质网脂质翻转酶 TMEM16K 是内溶酶体途径的细胞器间调节剂。我们通过邻近生物素化蛋白质组学分析确定了内体运输是 TMEM16K 的主要功能簇。TMEM16K 与内体形成接触位点，用小 GTP 酶 RAB7 重新构成分裂 GFP。我们的研究进一步表明 TMEM16K 的脂质翻转活性在这些部位的内体分拣中起作用。TMEM16K 功能丧失导致内体逆行运输和神经肌肉功能受损，这是 SCAR10 的症状之一。因此，含有 TMEM16K 的内质网-内体接触位点代表了调节内体分拣的具有临床相关性的平台。
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