title: Bilateral inhibition of HAUSP deubiquitinase by a viral interferon regulatory factor protein.
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.
authors: Department of Molecular Microbiology and Immunology, Keck School of Medicine, University of Southern California, Los Angeles, California, USA.
authors: Hye-Ra
authors: HR
authors: Lee
authors: Won-Chan
authors: WC
authors: Choi
authors: Stacy
authors: S
authors: Lee
authors: Jungwon
authors: J
authors: Hwang
authors: Eunha
authors: E
authors: Hwang
authors: Koushik
authors: K
authors: Guchhait
authors: Juergen
authors: J
authors: Haas
authors: Zsolt
authors: Z
authors: Toth
authors: Young Ho
authors: YH
authors: Jeon
authors: Tae-Kwang
authors: TK
authors: Oh
authors: Myung Hee
authors: MH
authors: Kim
authors: Jae U
authors: JU
authors: Jung
mesh_terms: D000818:Animals; D017209:Apoptosis; D001665:Binding Sites; D059447:Cell Cycle Checkpoints; D045744:Cell Line, Tumor; D057809:HEK293 Cells; D018259:Herpesvirus 1, Human / Q000378:metabolism; D006801:Humans; D050835:Interferon Regulatory Factors / Q000737:chemistry* / Q000378:metabolism; D054685:Lymphoma, Primary Effusion / Q000188:drug therapy / Q000473:pathology; D051379:Mice; D016688:Mice, Inbred NOD; D016513:Mice, SCID; D019906:Nuclear Magnetic Resonance, Biomolecular; D010455:Peptides / Q000627:therapeutic use; D017434:Protein Structure, Tertiary; D051736:Proto-Oncogene Proteins c-mdm2 / Q000737:chemistry / Q000378:metabolism; D016159:Tumor Suppressor Protein p53 / Q000737:chemistry / Q000378:metabolism; D043222:Ubiquitin Thiolesterase / Q000037:antagonists & inhibitors / Q000737:chemistry* / Q000502:physiology; D000076084:Ubiquitin-Specific Peptidase 7; D054875:Ubiquitination; D014764:Viral Proteins / Q000737:chemistry* / Q000378:metabolism; D023041:Xenograft Model Antitumor Assays
chemical_list: D050835:Interferon Regulatory Factors; D010455:Peptides; D016159:Tumor Suppressor Protein p53; D014764:Viral Proteins; C413486:viral interferon regulatory factors; C497206:MDM2 protein, human; D051736:Proto-Oncogene Proteins c-mdm2; C464569:USP7 protein, human; D043222:Ubiquitin Thiolesterase; D000076084:Ubiquitin-Specific Peptidase 7