The Hace1 E3 ligase: linking misfolded protein load and oncogenesis

Hace1 is a new member of the HECT family of E3 protein‐ubiquitin ligases. We previously showed that the Hace1 gene is a tumor suppressor that is inactivated in human Wilms' tumor, and that Hace1‐/‐ mice develop spontaneous tumors. Moreover, various stresses dramatically increases tumor incidence in these mice. The goal of this study is to characterize the role Hace1 is playing in cellular stress and more specifically in misfolded protein handling by the cell. We now show that Hace1 decreases the half‐life of GFP‐Huntingtin‐128Q and eliminates its aggregates in a proteasome independent manner. This indicates that Hace1 may mediate mutant Huntingtin degradation via other pathways such as autophagy. Indeed, Hace1‐/‐ cells show decreased autophagy induction. Fluorescence microscopy suggests that Hace1 is localized to a recently described cellular structure known as IPOD‐ Insoluble Protein Deposit. Using fluorescence recovery after photo‐bleaching we determined that GFP‐Hace1 interacts with IPOD in a highly dynamic manner suggesting that Hace1 plays a role in the function of IPOD rather than being transported to them as aggregates. Taken together, these data indicate that the tumor suppressor Hace1 reduces accumulation of misfolded proteins by promoting autophagy, suggesting that the deregulation of non‐proteasomal processes that manage misfolded protein load may promote oncogenesis in the cell.