A cellular system that degrades misfolded proteins and protects against neurodegeneration.

Abstract	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.
Authors	Lili Guo, Benoit I Giasson, Alex Glavis-Bloom, Michael D Brewer, James Shorter, Aaron D Gitler, Xiaolu Yang
Journal	Molecular cell (Mol Cell) Vol. 55 Issue 1 Pg. 15-30 (Jul 03 2014) ISSN: 1097-4164 [Electronic] United States
PMID	24882209 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
Copyright	Copyright © 2014 Elsevier Inc. All rights reserved.
Chemical References	ATXN1 protein, human Ataxin-1 Ataxins Atxn1 protein, mouse Nerve Tissue Proteins Nuclear Proteins Promyelocytic Leukemia Protein RNF4 protein, human Transcription Factors Tumor Suppressor Proteins Ubiquitin PML protein, human Proteasome Endopeptidase Complex
Topics	Animals Ataxin-1 Ataxins Humans Mice Models, Biological Nerve Degeneration (pathology) Nerve Tissue Proteins (metabolism) Nuclear Proteins (metabolism, physiology) Promyelocytic Leukemia Protein Proteasome Endopeptidase Complex Protein Folding Proteolysis Spinocerebellar Ataxias (genetics, metabolism) Sumoylation Transcription Factors (metabolism, physiology) Tumor Suppressor Proteins (metabolism, physiology) Ubiquitin Ubiquitination

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