Department of Pharmacology and Center for Neurodegenerative Disease, Emory University School of Medicine, Atlanta, GA 30322, USA.
J Cell Biol. 2012 Nov 26;199(5):799-816. doi: 10.1083/jcb.201204137. Epub 2012 Nov 19.
Mutations in small integral membrane protein of lysosome/late endosome (SIMPLE) cause autosomal dominant, Charcot-Marie-Tooth disease (CMT) type 1C. The cellular function of SIMPLE is unknown and the pathogenic mechanism of SIMPLE mutations remains elusive. Here, we report that SIMPLE interacted and colocalized with endosomal sorting complex required for transport (ESCRT) components STAM1, Hrs, and TSG101 on early endosomes and functioned with the ESCRT machinery in the control of endosome-to-lysosome trafficking. Our analyses revealed that SIMPLE was required for efficient recruitment of ESCRT components to endosomal membranes and for regulating endosomal trafficking and signaling attenuation of ErbB receptors. We found that the ability of SIMPLE to regulate ErbB trafficking and signaling was impaired by CMT-linked SIMPLE mutations via a loss-of-function, dominant-negative mechanism, resulting in prolonged activation of ERK1/2 signaling. Our findings indicate a function of SIMPLE as a regulator of endosomal trafficking and provide evidence linking dysregulated endosomal trafficking to CMT pathogenesis.
溶酶体/晚期内体小整合膜蛋白（SIMPLE）的突变导致常染色体显性遗传的腓骨肌萎缩症（CMT）1C 型。SIMPLE 的细胞功能尚不清楚，SIMPLE 突变的致病机制仍不清楚。在这里，我们报告 SIMPLE 与内体运输所需的分选连接复合体（ESCRT）成分 STAM1、Hrs 和 TSG101 在早期内体上相互作用和共定位，并与 ESCRT 机制一起控制内体到溶酶体的运输。我们的分析表明，SIMPLE 对于 ESCRT 成分有效招募到内体膜以及调节内体运输和 ERB 受体信号衰减是必需的。我们发现，CMT 相关的 SIMPLE 突变通过功能丧失的显性负作用机制削弱了 SIMPLE 调节 ErbB 运输和信号的能力，导致 ERK1/2 信号的持续激活。我们的研究结果表明 SIMPLE 作为内体运输调节剂的功能，并为失调的内体运输与 CMT 发病机制之间的联系提供了证据。
