Tumor necrosis factor receptor-associated factor 6 (TRAF6) associates with Huntingtin protein and promotes its atypical ubiquitination to enhance aggregate formation

Silvia Zucchelli, Federica Marcuzzi, Marta Codrich, Elena Agostoni, Sandra Vilotti, Marta Biagioli, Milena Pinto, Alisia Carnemolla, Claudio Santoro, Stefano Gustincich, Francesca Persichetti

Research output: Contribution to journalArticlepeer-review

46 Scopus citations

Abstract

Huntington disease (HD) is a neurodegenerative disorder caused by an expansion of polyglutamines in the first exon of huntingtin (HTT), which confers aggregation-promoting properties to amino-terminal fragments of the protein (N-HTT). Mutant N-HTT aggregates are enriched for ubiquitin and contain ubiquitin E3 ligases, thus suggesting a role for ubiquitination in aggregate formation. Here, we report that tumor necrosis factor receptor-associated factor 6 (TRAF6) binds to WT and polyQ-expanded N-HTT in vitro as well as to endogenous full-length proteins in mouse and human brain in vivo. Endogenous TRAF6 is recruited to cellular inclusions formed by mutant N-HTT. Transient overexpression of TRAF6 promotes WT and mutant N-HTT atypical ubiquitination with Lys 6, Lys 27, and Lys 29 linkage formation. Both interaction and ubiquitination seem to be independent from polyQ length. In cultured cells, TRAF6 enhances mutant N-HTT aggregate formation, whereas it has no effect on WT N-HTT protein localization. Mutant N-HTT inclusions are enriched for ubiquitin staining only when TRAF6 and Lys 6, Lys 27, and Lys 29 ubiquitin mutants are expressed. Finally, we show that TRAF6 is up-regulated in postmortem brains from HD patients where it is found in the insoluble fraction. These results suggest that TRAF6 atypical ubiquitination warrants investigation in HD pathogenesis.

Original languageEnglish (US)
Pages (from-to)25108-25117
Number of pages10
JournalJournal of Biological Chemistry
Volume286
Issue number28
DOIs
StatePublished - Jul 15 2011
Externally publishedYes

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Cell Biology

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