title: Kaposi's sarcoma-associated herpesvirus K7 protein targets a ubiquitin-like/ubiquitin-associated domain-containing protein to promote protein degradation.
abstract: Pathogens exploit host machinery to establish an environment that favors their propagation. Because of their pivotal roles in cellular physiology, protein degradation pathways are common targets for viral proteins. Protein-linking integrin-associated protein and cytoskeleton 1 (PLIC1), also called ubiquilin, contains an amino-terminal ubiquitin-like (UBL) domain and a carboxy-terminal ubiquitin-associated (UBA) domain. PLIC1 is proposed to function as a regulator of the ubiquitination complex and proteasome machinery. Kaposi's sarcoma-associated herpesvirus (KSHV) contains a small membrane protein, K7, that protects cells from apoptosis induced by various stimuli. We report here that cellular PLIC1 is a K7-interacting protein and that the central hydrophobic region of K7 and the carboxy-terminal UBA domain of PLIC1 are responsible for their interaction. Cellular PLIC1 formed a dimer and bound efficiently to polyubiquitinated proteins through its carboxy-terminal UBA domain, and this activity correlated with its ability to stabilize cellular I kappa B protein. In contrast, K7 interaction prevented PLIC1 from forming a dimer and binding to polyubiquitinated proteins, leading to the rapid degradation of I kappa B. Furthermore, K7 expression promoted efficient degradation of the p53 tumor suppressor, resulting in inhibition of p53-mediated apoptosis. These results indicate that KSHV K7 targets a regulator of the ubiquitin- and proteasome-mediated degradation machinery to deregulate cellular protein turnover, which potentially provides a favorable environment for viral reproduction.
authors.affiliation: Department of Microbiology and Molecular Genetics and Tumor Virology Division, New England Primate Research Center, Harvard Medical School, Southborough, Massachusetts 01772, USA.
authors.forename: Pinghui
authors.initials: P
authors.lastname: Feng
authors.forename: Christopher W
authors.initials: CW
authors.lastname: Scott
authors.forename: Nam-Hyuk
authors.initials: NH
authors.lastname: Cho
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Nakamura
authors.forename: Young-Hwa
authors.initials: YH
authors.lastname: Chung
authors.forename: Mervyn J
authors.initials: MJ
authors.lastname: Monteiro
authors.forename: Jae U
authors.initials: JU
authors.lastname: Jung
mesh_terms: D048868:Adaptor Proteins, Signal Transducing; D000818:Animals; D000071183:Autophagy-Related Proteins; D002352:Carrier Proteins / Q000235:genetics / Q000378:metabolism*; D018797:Cell Cycle Proteins; D002460:Cell Line; D003546:Cysteine Endopeptidases / Q000378:metabolism; D019281:Dimerization; D019288:Herpesvirus 8, Human / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D020672:I-kappa B Proteins / Q000378:metabolism; D024101:Mitochondrial Proteins / Q000235:genetics / Q000378:metabolism*; D009097:Multienzyme Complexes / Q000378:metabolism; D000072000:NF-KappaB Inhibitor alpha; D046988:Proteasome Endopeptidase Complex; D017434:Protein Structure, Tertiary; D011993:Recombinant Fusion Proteins / Q000378:metabolism; D020798:Two-Hybrid System Techniques; D014452:Ubiquitins / Q000235:genetics / Q000378:metabolism*; D014764:Viral Proteins / Q000235:genetics / Q000378:metabolism*
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D000071183:Autophagy-Related Proteins; D002352:Carrier Proteins; D018797:Cell Cycle Proteins; D020672:I-kappa B Proteins; C468524:K7 protein, Human herpesvirus 8; D024101:Mitochondrial Proteins; D009097:Multienzyme Complexes; C000606204:NFKBIA protein, human; D011993:Recombinant Fusion Proteins; C107792:UBQLN1 protein, human; D014452:Ubiquitins; D014764:Viral Proteins; D000072000:NF-KappaB Inhibitor alpha; D003546:Cysteine Endopeptidases; D046988:Proteasome Endopeptidase Complex