Identification of NUB1 as a Suppressor of Mutant Huntingtin Toxicity via Enhanced Protein Clearance

Huntington’s disease is caused by expanded CAG in HTT, conferring toxic gain of function to mutant HTT (mHTT) protein. Reducing mHTT levels is postulated as a strategy for therapeutic intervention. We conducted genome-wide RNAi screens for genes modifying mHTT levels and identified 13 hits. Ten were tested in vivo in a Drosophila Huntington’s disease model and 6 exhibited activity consistent with in vitro screening. Among these, NUB1 overexpression lowered mHTT in neuronal models, and rescued mHTT-induced death. NUB1 reduces mHTT level by enhancing poly-ubiquitination 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 modulate NUB1 for treatment, interferon beta (IFNβ) lowered mHTT and rescued neuronal toxicity via 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