Bilateral inhibition of HAUSP deubiquitinase by a viral interferon regulatory factor protein

Hye-Ra Lee, Won-Chan Choi, Stacy Lee, Jungwon Hwang, Eunha Hwang, Koushik Guchhait, Juergen Haas, Zsolt Toth, Young Ho Jeon, Tae-Kwang Oh, Myung Hee Kim, Jae U Jung

Research output: Contribution to journalArticlepeer-review

Abstract

Herpesvirus-associated ubiquitin-specific protease (HAUSP) regulates the stability of p53 and the p53-binding protein MDM2, implicating HAUSP as a therapeutic target for tuning p53-mediated antitumor activity. Here we report the structural analysis of HAUSP with Kaposi's sarcoma-associated herpesvirus viral interferon (IFN) regulatory factor 4 (vIRF4) and the discovery of two vIRF4-derived peptides, vif1 and vif2, as potent and selective HAUSP antagonists. This analysis reveals a bilateral belt-type interaction that results in inhibition of HAUSP. The vif1 peptide binds the HAUSP TRAF domain, competitively blocking substrate binding, whereas the vif2 peptide binds both the HAUSP TRAF and catalytic domains, robustly suppressing its deubiquitination activity. Peptide treatments comprehensively blocked HAUSP, leading to p53-dependent cell-cycle arrest and apoptosis in culture and to tumor regression in xenograft mouse model. Thus, the virus has developed a unique strategy to target the HAUSP-MDM2-p53 pathway, and these virus-derived short peptides represent biologically active HAUSP antagonists.
Original languageEnglish
Pages (from-to)1336-44
Number of pages9
JournalNature Structural & Molecular Biology
Volume18
Issue number12
DOIs
Publication statusPublished - 2011

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