期刊
MOLECULAR CELL
卷 55, 期 1, 页码 15-30出版社
CELL PRESS
DOI: 10.1016/j.molcel.2014.04.030
关键词
-
资金
- NIH [CA088868, GM060911]
- Penn Medicine Neuroscience Center (PMNC)
- Penn Center for AIDS Research (CFAR), NIH [P30 AI045008]
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.
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