Title: Post-translational events underlying the pathogenesis of vGPCR Human gamma herpesviruses such as Kaposi's sarcoma (KS)-associated herpesvirus (KSHV) are often associated with infection of immunodeficiency virus-1 and induce tumor in patients. In addition to latent proteins, KSHV lytic proteins have been demonstrated to possess tumorigenic or growth-promoting activities, indicating that lytic replication may contribute to the disease progression of KS and other KSHV-associated malignancies. One intriguing example is the KSHV-encoded G protein-coupled receptor (vGPCR). Although tumorigenicity and signaling events downstream of vGPCR are better defined, it is not clear how vGPCR is regulated. In fact, continuous expression of constitutively active GPCRs (e.g., vGPCR or retinal rhodopsin) induced cell death in mammalian cells, raising the possibility that KSHV has evolved mechanisms to control vGPCR expression and activity. Our preliminary study discovered that the K7 membrane protein interacts with vGPCR and induces its proteasome degradation. Furthermore, K7 retains vGPCR in the ER and increases vGPCR ubiquitination. We hypothesize that K7 induces the ER- associated degradation of vGPCR and functions as a negative regulator for vGPCR tumorigenesis. Our study proposes to elucidate the molecular action of K7 in routing vGPCR to the ER-associated degradation. We will employ both genetic and biochemical assays to identify cellular factors and characterize their roles in K7-induced vGPCR degradation. These experiments not only will elucidate the intracellular regulation of vGPCR, but also will reveal cellular molecules that can be potentially targeted for anti- viral therapy.

Public Health Relevance

Human herpesviruses such as Kaposi's sarcoma-associated herpesvirus (KSHV) induce tumor in patients under conditions of immunodeficiency. KSHV has various gene products that are capable of promoting tumor formation. This study proposes to investigate how one of these viral proteins, the KSHV G protein-coupled receptor, is regulated at the post-translational level.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA134241-06
Application #
8460123
Study Section
AIDS-associated Opportunistic Infections and Cancer Study Section (AOIC)
Program Officer
Read-Connole, Elizabeth Lee
Project Start
2009-06-10
Project End
2014-04-30
Budget Start
2013-05-01
Budget End
2014-04-30
Support Year
6
Fiscal Year
2013
Total Cost
$310,286
Indirect Cost
$121,087
Name
University of Southern California
Department
Microbiology/Immun/Virology
Type
Schools of Medicine
DUNS #
072933393
City
Los Angeles
State
CA
Country
United States
Zip Code
90089
Zhang, Junjie; Feng, Hao; Xu, Simin et al. (2016) Hijacking GPCRs by viral pathogens and tumor. Biochem Pharmacol 114:69-81
Zhao, Jun; Li, Junhua; Xu, Simin et al. (2016) Emerging Roles of Protein Deamidation in Innate Immune Signaling. J Virol 90:4262-8
Zhang, Junjie; Zhu, Lining; Lu, Xiaolu et al. (2015) Recombinant Murine Gamma Herpesvirus 68 Carrying KSHV G Protein-Coupled Receptor Induces Angiogenic Lesions in Mice. PLoS Pathog 11:e1005001
Zhao, Jun; He, Shanping; Minassian, Arlet et al. (2015) Recent advances on viral manipulation of NF-κB signaling pathway. Curr Opin Virol 15:103-11
He, Shanping; Zhao, Jun; Song, Shanshan et al. (2015) Viral pseudo-enzymes activate RIG-I via deamidation to evade cytokine production. Mol Cell 58:134-46
Zhang, Junjie; He, Shanping; Wang, Yi et al. (2015) Herpesviral G protein-coupled receptors activate NFAT to induce tumor formation via inhibiting the SERCA calcium ATPase. PLoS Pathog 11:e1004768
Brulois, Kevin; Wong, Lai-Yee; Lee, Hye-Ra et al. (2015) Association of Kaposi's Sarcoma-Associated Herpesvirus ORF31 with ORF34 and ORF24 Is Critical for Late Gene Expression. J Virol 89:6148-54
Minassian, Arlet; Zhang, Junjie; He, Shanping et al. (2015) An Internally Translated MAVS Variant Exposes Its Amino-terminal TRAF-Binding Motifs to Deregulate Interferon Induction. PLoS Pathog 11:e1005060
Zhang, Junjie; Zhu, Lining; Feng, Pinghui (2014) Dissecting innate immune signaling in viral evasion of cytokine production. J Vis Exp :
Feng, Pinghui; Moses, Ashlee; Früh, Klaus (2013) Evasion of adaptive and innate immune response mechanisms by γ-herpesviruses. Curr Opin Virol 3:285-95

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