A cellular system that degrades misfolded proteins and protects against neurodegeneration

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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Ataxin-1
  • Ataxins
  • Humans
  • Mice
  • Models, Biological
  • Nerve Degeneration / pathology*
  • Nerve Tissue Proteins / metabolism
  • Nuclear Proteins / metabolism
  • Nuclear Proteins / physiology
  • Promyelocytic Leukemia Protein
  • Proteasome Endopeptidase Complex
  • Protein Folding*
  • Proteolysis*
  • Spinocerebellar Ataxias / genetics
  • Spinocerebellar Ataxias / metabolism
  • Sumoylation
  • Transcription Factors / metabolism
  • Transcription Factors / physiology
  • Tumor Suppressor Proteins / metabolism
  • Tumor Suppressor Proteins / physiology
  • Ubiquitin
  • Ubiquitination


  • 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