Chin Lih-Shen, Lee Samuel M, Li Lian
Department of Pharmacology; Emory University School of Medicine; Atlanta, GA USA.
Commun Integr Biol. 2013 May 1;6(3):e24214. doi: 10.4161/cib.24214. Epub 2013 Apr 9.
SIMPLE, also known as LITAF, EET1 and PIG7, was originally identified based on its transcriptional upregulation by estrogen, p53, lipopolysaccharide or a microbial cell-wall component. Missense mutations in SIMPLE cause Charcot-Marie-Tooth disease (CMT), and altered SIMPLE expression is associated with cancer, obesity and inflammatory bowel diseases. Despite increasing evidence linking SIMPLE to human diseases, the biological function of SIMPLE is unknown and the pathogenic mechanism of SIMPLE mutations remains elusive. Our recent study reveals that SIMPLE is a functional partner of the endosomal sorting complex required for transport (ESCRT) machinery in the regulation of endosome-to-lysosome trafficking and intracellular signaling. Our results indicate that CMT-linked SIMPLE mutants are loss-of-function mutants which act dominantly to impair endosomal trafficking and signaling attenuation. We propose that endosomal trafficking and signaling dysregulation is a key pathogenic mechanism in CMT and other diseases that involve SIMPLE dysfunction.
SIMPLE，也被称为LITAF、EET1和PIG7，最初是基于其在雌激素、p53、脂多糖或微生物细胞壁成分作用下的转录上调而被鉴定出来的。SIMPLE中的错义突变会导致夏科-马里-图斯病（CMT），而SIMPLE表达的改变与癌症、肥胖症和炎症性肠病有关。尽管有越来越多的证据将SIMPLE与人类疾病联系起来，但SIMPLE的生物学功能尚不清楚，SIMPLE突变的致病机制仍然难以捉摸。我们最近的研究表明，在调节内体到溶酶体的运输和细胞内信号传导过程中，SIMPLE是转运所需内体分选复合体（ESCRT）机制的功能伙伴。我们的结果表明，与CMT相关的SIMPLE突变体是功能丧失突变体，它们主要通过损害内体运输和信号衰减来发挥作用。我们提出，内体运输和信号失调是CMT以及其他涉及SIMPLE功能障碍疾病的关键致病机制。
