Human Kaposi’s sarcoma-associated herpesvirus (KSHV), along with Epstein-Barr virus, belongs to the lymphocryptic gamma-herpesvirinae. In immunocompromised individuals, KSHV infection is causatively linked to Kaposi’s sarcoma, primary effusion lymphoma (PEL), and Multicentric Castleman’s disease (MCD). Whereas Kaposi’s sarcoma is believed to have an endothelial cell origin, PEL and MCD are B cell-derived malignancies. These KSHV-associated malignancies are angiogenic lesions elicited by proinflammatory responses. Indeed, the KSHV genome encodes various cytokines/ chemokines or their receptors, all of which contribute directly or indirectly to the proinflammatory response during viral infection. These viral polypeptides are homologous to their cellular counterparts, although their functionality may be distinct. Additionally, as a successful pathogen, KSHV expresses an array of immunomodulatory proteins that assist the virus to evade and regulate host immune responses. The research of my laboratory focuses on viral immune evasion strategies and tumorigenicities of KSHV proteins that likely engender KSHV-associated malignancies.
Herpesviruses establish life-long persistent infections in their hosts. In order to persist, viruses have evolved elaborate mechanisms to evade host immune response. Virus-infected cells often are induced to undergo apoptosis as one form of host innate immunity. To counter programmed cell death that ultimately will destroy the infecting virus, herpesviruses dedicate a number of gene products to delay or abort cellular apoptotic pathways. A notable example is a homolog of Bcl-2, encoded by all gamma-herpesviruses, which likely is involved in viral latency establishment or reactivation. We have identified two novel mitochondrial or ER membrane proteins that differentially inhibit intracellular apoptotic pathways, thereby ensuring productive viral replication and likely facilitating viral dissemination within the host. Our ongoing efforts will continue to identify other novel viral proteins and characterize the molecular mechanisms and pathways by which such viral proteins interact with cellular apoptotic components. My lab is also interested in manipulating the cellular apoptotic pathways to induce cell death in KSHV-associated lymphoma cell lines, which may have important therapeutic applications in the future.
Among the proinflammatory proteins of KSHV, an intriguing example is the viral G protein-coupled receptor (vGPCR) that activates multiple signaling pathways to promote inflammation and angiogenesis. Although signal transduction and tumorigenicity of this particular vGPCR have been studied, its regulation remains largely unknown. vGPCR is a IL-8 receptor homolog and is constitutively active in the absence of cognate ligand binding. Increasing evidence suggests that the tight regulation of vGPCR in vivo is important for its tumorigenicity (in a mouse model). Intriguingly, vGPCR is scarcely, yet more commonly, expressed within early lesions, suggesting that it likely provokes proinflammatory responses through both paracrine and autocrine effects; this has implications for potential relationships between deregulating mechanisms and disease prognosis. My recent studies have revealed that KSHV perhaps has evolved two types of regulatory components that function in trans and in cis. The cis elements are located in the N-terminal sequences of vGPCR and consist of primary amino acid (YDY, NxT/S) sequences and post-translational modification (tyrosine sulfation, glycosylation) signals carried within, whereas chemokines and viral factors represent the trans components that regulate vGPCR via diverse mechanisms. Consequently, my lab is investigating the regulatory events that contribute to vGPCR-mediated signaling and tumorigenicity and we seek to understand how this signaling chemokine receptor is differentially regulated by various factors. These studies may reveal important new insights into complex regulatory mechanisms that, in turn, govern the deregulated expression of vGPCR.
Projects in my lab involve techniques of molecular virology, cell biology, and biochemistry to study human KSHV and mouse gamma-herpesvirus 68 (gmmaHV-68). gammaHV-68, which is closely related to human KSHV, has a replication system and a tractable animal host. While standard molecular biology techniques are used to study viral protein function in vitro, the development of bacterial artificial chromosome (Bac) systems also allows us to manipulate viral genomes in E. coli and generate mutant viruses in mammalian cells. In the case of gammaHV-68, mutant viruses will be used to infect laboratory mice and the viral life cycles of such mutants will be assessed. Our ultimate goal is to understand the molecular events underlying KSHV-associated malignancies and identify new potential targets that may be exploited for new antiviral therapeutic modalities.
RESEARCH INTERESTS
Host recognition and virus escape
Gamma herpesvirus infection under immunosuppression
Pathogenesis of human Kaposi's sarcoma-associated herpesvirus
RECENT PUBLICATIONS
Liang, C.Y., Feng, P., Ku, B., Dotan, I., Canaani, D., Oh, B.-H., Jung, J.U., "Autophagic and tumor suppressor activity of a Beclin1-binding UVRAG" Nat. Cell Biol., 8:688-99, 2006
Feng, P., Liang, C.Y., Shin, Y.C., and Jung, J.U., "A novel inhibitory mechanism of the mitochondrion-mediated apoptosis by a herpesviral protein" PLoS Pathog., 3(12):e174, December 2007
Feng H, Dong X, Negaard A, and Feng P, "Kaposi’s sarcoma-associated herpesvirus K7 induces viral G protein-coupled receptor degradation and reduces its tumorigenicity." PLoS Pathog., 4(9):e157, September 2008
SIGNIFICANT PUBLICATIONS
Feng H, Dong X, Negaard A, and Feng P, "Kaposi’s sarcoma-associated herpesvirus K7 induces viral G protein-coupled receptor degradation and reduces its tumorigenicity." PLoS Pathog., 4(9):e157, September 2008
Feng, P., Liang, C.Y., Shin, Y.C., and Jung, J.U., "A novel inhibitory mechanism of the mitochondrion-mediated apoptosis by a herpesviral protein" PLoS Pathog., 3(12):e174, December 2007
Liang, C.Y., Feng, P., Ku, B., Dotan, I., Canaani, D., Oh, B.-H., Jung, J.U., "Autophagic and tumor suppressor activity of a Beclin1-binding UVRAG" Nat. Cell Biol., 8:688-699, 2006
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