Identification of NUB1 as a suppressor of mutant Huntington toxicity via enhanced protein clearance

Nat Neurosci. 2013 May;16(5):562-70. doi: 10.1038/nn.3367. Epub 2013 Mar 24.


Huntington's disease is caused by expanded CAG repeats in HTT, conferring toxic gain of function on mutant HTT (mHTT) protein. Reducing mHTT amounts is postulated as a strategy for therapeutic intervention. We conducted genome-wide RNA interference screens for genes modifying mHTT abundance and identified 13 hits. We tested 10 in vivo in a Drosophila melanogaster Huntington's disease model, and 6 exhibited activity consistent with the in vitro screening results. Among these, negative regulator of ubiquitin-like protein 1 (NUB1) overexpression lowered mHTT in neuronal models and rescued mHTT-induced death. NUB1 reduces mHTT amounts by enhancing polyubiquitination and proteasomal degradation of mHTT protein. The process requires CUL3 and the ubiquitin-like protein NEDD8 necessary for CUL3 activation. As a potential approach to modulating NUB1 for treatment, interferon-β lowered mHTT and rescued neuronal toxicity through induction of NUB1. Thus, we have identified genes modifying endogenous mHTT using high-throughput screening and demonstrate NUB1 as an exemplar entry point for therapeutic intervention of Huntington's disease.

Publication types

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

MeSH terms

  • Adaptor Proteins, Signal Transducing
  • Adenosine Triphosphate / metabolism
  • Animals
  • Cell Line
  • Cells, Cultured
  • Cullin Proteins / metabolism
  • Disease Models, Animal
  • Drosophila / drug effects
  • Drosophila / metabolism
  • Embryo, Mammalian
  • Female
  • Gene Expression
  • Genome-Wide Association Study
  • Humans
  • Huntingtin Protein
  • Huntington Disease / pathology
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Mice, Transgenic
  • Mutation / genetics*
  • NEDD8 Protein
  • Nerve Tissue Proteins / genetics
  • Nerve Tissue Proteins / metabolism*
  • Nerve Tissue Proteins / toxicity
  • Neurons / drug effects
  • Neurons / metabolism*
  • Pregnancy
  • Transcription Factors / genetics
  • Transcription Factors / metabolism*
  • Ubiquitins / metabolism


  • Adaptor Proteins, Signal Transducing
  • CUL3 protein, human
  • Cullin Proteins
  • FAT10 protein, mouse
  • HTT protein, human
  • Huntingtin Protein
  • NEDD8 Protein
  • NUB1 protein, human
  • Nedd8 protein, mouse
  • Nerve Tissue Proteins
  • Transcription Factors
  • Ubiquitins
  • Adenosine Triphosphate