Abstract
The Kaposi's sarcoma-associated herpesvirus (KSHV) genome encodes a G protein-coupled receptor (vGPCR). vGPCR is a ligand-independent, constitutively active signaling molecule that promotes cell growth and proliferation; however, it is not clear how vGPCR is negatively regulated. We report here that the KSHV K7 small membrane protein interacts with vGPCR and induces its degradation, thereby dampening vGPCR signaling. K7 interaction with vGPCR is readily detected in transiently transfected human cells. Mutational analyses reveal that the K7 transmembrane domain is necessary and sufficient for this interaction. Biochemical and confocal microscopy studies indicate that K7 retains vGPCR in the endoplasmic reticulum (ER) and induces vGPCR proteasomeal degradation. Indeed, the knockdown of K7 by shRNA-mediated silencing increases vGPCR protein expression in BCBL-1 cells that are induced for KSHV lytic replication. Interestingly, K7 expression significantly reduces vGPCR tumorigenicity in nude mice. These findings define a viral factor that negatively regulates vGPCR protein expression and reveal a post-translational event that modulates GPCR-dependent transformation and tumorigenicity.
Highlights
Kaposi’s sarcoma-associated herpesvirus (KSHV, known as human herpesvirus 8) is believed to be the etiologic agent for Kaposi’s sarcoma (KS) [1]
KSHV is found in primary effusion lymphoma and multicentric Castleman’s disease, rare lymphoproliferative diorders associated with immuno-suppression
The KSHV genome encodes a G protein-coupled receptor that is believed to contribute to the KSHV-associated malignancies. vGPCR is a ligand-independent, constitutively active signaling molecule
Summary
Kaposi’s sarcoma-associated herpesvirus (KSHV, known as human herpesvirus 8) is believed to be the etiologic agent for Kaposi’s sarcoma (KS) [1]. The KSHV genome encodes over 80 viral polypeptides, many of which are capable of promoting cell proliferation and/or modulating host responses, when expressed in gene transfer experiments (for review see reference [5]). One such gene product consistently detected in KS lesions is the viral G protein-coupled receptor (vGPCR, or open reading frame 74) [6,7]. VGPCR is predominantly translated from a bicistronic mRNA transcript downstream of K14 (vOX2), presumably reducing vGPCR protein expression [6,20] These observations suggest that KSHV likely has evolved mechanisms to achieve a temporary expression of the constitutively active vGPCR during lytic infection.
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