A Cellular System that Degrades Misfolded Proteins and Protects against Neurodegeneration

• Published in: Molecular cell Vol. 55; no. 1; pp. 15 - 30
• Main Authors: Guo, Lili, Giasson, Benoit I., Glavis-Bloom, Alex, Brewer, Michael D., Shorter, James, Gitler, Aaron D., Yang, Xiaolu
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 03.07.2014
• Subjects: animal models; Animals; ataxia (disorder); Ataxin-1; Ataxins; cell nucleus; Humans; mammals; Mice; Models, Biological; Nerve Degeneration - pathology; Nerve Tissue Proteins - metabolism; neurodegenerative diseases; Nuclear Proteins - metabolism; Nuclear Proteins - physiology; Promyelocytic Leukemia Protein; Proteasome Endopeptidase Complex; Protein Folding; proteins; Proteolysis; Spinocerebellar Ataxias - genetics; Spinocerebellar Ataxias - metabolism; Sumoylation; Transcription Factors - metabolism; Transcription Factors - physiology; Tumor Suppressor Proteins - metabolism; Tumor Suppressor Proteins - physiology; Ubiquitin; ubiquitin-protein ligase; Ubiquitination
• ISSN: 1097-2765; 1097-4164; 1097-4164
• DOI: 10.1016/j.molcel.2014.04.030

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. [Display omitted] •PML reduces various misfolded proteins in the mammalian cell nucleus•PML binds to misfolded proteins via substrate recognition sites and SUMOylates them•SUMOylated misfolded proteins are ubiquitinated by RNF4 for proteasomal degradation•PML deficiency exacerbates phenotypes of a mouse neurodegeneration model Misfolded proteins cause disease, and it remains unclear how they are selectively degraded. Here, Guo et al. show how misfolded proteins are removed from mammalian cell nuclei, defining the mechanism and its role in protection against neurodegeneration.