一种能降解错误折叠蛋白并预防神经退行性疾病的细胞系统。
A cellular system that degrades misfolded proteins and protects against neurodegeneration.
机构信息
Department of Cancer Biology and Abramson Family Cancer Research Institute, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA.
Department of Pharmacology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA.
出版信息
Mol Cell. 2014 Jul 3;55(1):15-30. doi: 10.1016/j.molcel.2014.04.030. Epub 2014 May 29.
Misfolded proteins compromise cellular function and cause disease. How these proteins are detected and degraded is not well understood. Here we show that PML/TRIM19 and the SUMO-dependent ubiquitin ligase RNF4 act together to promote the degradation of misfolded proteins in the mammalian cell nucleus. PML selectively interacts with misfolded proteins through distinct substrate recognition sites and conjugates these proteins with the small ubiquitin-like modifiers (SUMOs) through its SUMO ligase activity. SUMOylated misfolded proteins are then recognized and ubiquitinated by RNF4 and are subsequently targeted for proteasomal degradation. We further show that PML deficiency exacerbates polyglutamine (polyQ) disease in a mouse model of spinocerebellar ataxia 1 (SCA1). These findings reveal a mammalian system that removes misfolded proteins through sequential SUMOylation and ubiquitination and define its role in protection against protein-misfolding diseases.
错误折叠的蛋白质会损害细胞功能并导致疾病。然而，人们对于这些蛋白质是如何被检测和降解的仍知之甚少。本文中，我们发现 PML/TRIM19 和 SUMO 依赖性泛素连接酶 RNF4 可以共同促进哺乳动物细胞核中错误折叠蛋白质的降解。PML 通过其独特的底物识别位点选择性地与错误折叠的蛋白质相互作用，并通过其 SUMO 连接酶活性将这些蛋白质与小泛素样修饰物（SUMO）缀合。然后，SUMO 化的错误折叠蛋白质被 RNF4 识别和泛素化，并随后被靶向蛋白酶体降解。我们进一步发现，在脊髓小脑共济失调 1 型（SCA1）的小鼠模型中，PML 缺陷会加剧多聚谷氨酰胺（polyQ）疾病。这些发现揭示了一个通过顺序 SUMO 化和泛素化去除错误折叠蛋白质的哺乳动物系统，并定义了其在预防蛋白质错误折叠疾病中的作用。
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