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Abstract
Hye-Ra Lee1,8, Won-Chan Choi2,8, Stacy Lee1, Jungwon Hwang2,3, Eunha Hwang4, Koushik Guchhait2,5, Juergen Haas6, Zsolt Toth1, Young Ho Jeon4,7, Tae-Kwang Oh2, Myung Hee Kim2,5 & Jae U Jung1
1Department of Molecular Microbiology and Immunology, Keck School of Medicine, University of Southern California, Los Angeles, California, USA. 2Division of Biosystems Research, Korea Research Institute of Bioscience and Biotechnology, Daejeon, Korea. 3Department of Chemistry, Korea Advanced Institute of Science and Technology, Daejeon, Korea. 4Division of Magnetic Resonance, Korea Basic Science Institute, Ochang, Chungbuk, Korea. 5Biosystems and Bioengineering Program, University of Science and Technology, Daejeon, Korea. 6Max-von-Pettenkofer-Institut, Ludwig-Maximilians-Universitat Munchen, Munchen, Germany. 7College of Pharmacy, Korea University, Jochiwon, Chungnam, Korea. 8These authors contributed equally to this work. Correspondence should be addressed to
T.-K.O., M.H.K. or J.U.J.
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 1 and vif2, as potent and selective HAUSP antagonists. This analysis reveals a bilateral belt-type interaction that results in inhibition of HAUSP. The vif1 1 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.
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