HAUSP

HAUSP, short for herpesvirus-associated ubiquitin-specific protease, is a cysteine protease that removes ubiquitin from target proteins. It is encoded by the USP7 gene in humans and belongs to the ubiquitin-specific protease (USP) family of deubiquitinating enzymes. HAUSP has a broad range of substrates and participates in multiple cellular processes, including regulation of the p53 tumor suppressor pathway, the DNA damage response, chromatin remodeling, and innate immune signaling. The protein features an N-terminal TRAF-like domain that mediates interactions with various partners and a C-terminal catalytic domain responsible for deubiquitination.

In the p53/Mdm2 axis, HAUSP can deubiquitinate p53, stabilizing it, but it also deubiquitinates MDM2, stabilizing MDM2 and promoting p53 degradation; the net effect on p53 activity is context-dependent and influenced by cell type and signaling state. HAUSP activity and interactions are modulated by binding partners and post-translational modifications, and it can shuttle between cellular compartments, primarily the nucleus.

HAUSP was named for its association with herpesviruses; herpes simplex virus and related proteins can interact with USP7/HAUSP to modulate host antiviral responses and p53 signaling. In addition to viral interactions, USP7/HAUSP is a focus of cancer research due to its role in stabilizing MDM2 and regulating p53; inhibitors of USP7 are being explored as potential anticancer therapies to reactivate p53 in tumors that retain wild-type p53.

Overall, HAUSP/USP7 is a key regulator of protein ubiquitination dynamics with important implications for cell growth, stress responses, immunity, and viral infections.