Human gamma herpes viruses, Kaposi's sarcoma-associated herpesvirus (KSHV) and Epstein Barr virus (EBV), are often associated with infection of human immunodeficiency virus-1 (HIV-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. One intriguing example is the KSHV-encoded G protein-coupled receptor (kGPCR). kGPCR is a bona fide constitutively active signaling molecule and is capable of promoting host cell proliferation. Though signaling pathways have been extensively studied and accumulating data pointed kGPCR as the primary suspect of sarcomagenesis, it is not clear how kGPCR-induced signaling is negatively regulated after completion of activation cascades. In fact, prolonged activation imposes a stress and ultimately induces apoptosis in mammalian cells, raising the possibility that KSHV harbors viral protein(s) to fine tune kGPCR- induced signalling events. Our preliminary study discovered that a cellular PLIC-1 (proteasome ligase interaction component) interacts with kGPCR and guides its trafficking and turnover, therefore potentiates kGPCR-mediated signaling. In striking contrast, KSHV K7 induces kGPCR aberrant trafficking and degradation, dampening its downstream signaling pathways. The goal of this study is to characterize novel virus-host interactions during KSHV infection, focusing on the trafficking and turnover of kGPCR, which is regulated by a cellular PLIC-1 and the KSHV K7. In this proposal, we will investigate the mechanisms of PLIC-1 and the KSHV K7 proteins in regulating the stability, trafficking, and signaling activity of kGPCR. The combination of genetic, bio-chemical, and cellular experiments will provide insight into a novel viral strategy that governs kGPCR signaling and ultimately how kGPCR signaling contributes to the KSHV pathogenesis. ? ? ?
| Feng, Hao; Sun, Zhifeng; Farzan, Michael R et al. (2010) Sulfotyrosines of the Kaposi's sarcoma-associated herpesvirus G protein-coupled receptor promote tumorigenesis through autocrine activation. J Virol 84:3351-61 |
| Feng, Hao; Dong, Xiaonan; Negaard, Ashley et al. (2008) Kaposi's sarcoma-associated herpesvirus K7 induces viral G protein-coupled receptor degradation and reduces its tumorigenicity. PLoS Pathog 4:e1000157 |
