Disruption of Cellular RNA Processing by Kaposi's Sarcoma-Associated Herpesvirus

University Of California Berkeley, Berkeley CA

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Abstract

ABSTRACT Kaposi sarcoma-associated herpesvirus (KSHV) is the predominant etiologic agent of AIDS- associated cancers. It is endemic in many areas of Africa where, due to the extraordinarily high HIV burden, Kaposi sarcoma has emerged as one of the most common cancers. During AIDS-induced immunosuppression, KSHV replication is no longer effectively controlled, and, together with a large latently infected population of cells, contributes to disease progression and transmission. During lytic replication, KSHV dramatically remodels the host gene expression environment. A key player in this remodeling is the virally encoded, messenger RNA (mRNA) endonuclease termed SOX, which degrades cytoplasmic mRNA. SOX activity plays diverse roles in the gammaherpesvirus lifecycle and immune evasion. However, little is known about how the SOX protein is functionally regulated, either by the virus or by the host cell. Our preliminary data indicate that it is regulated both spatially and kinetically to balance the need for host shutoff against viral gene expression. In Aim I, we will define how these regulatory features impact SOX targeting of cellular and viral RNA transcripts throughout the course of KSHV lytic infection. SOX-induced cytoplasmic mRNA decay activates a feed forward loop that suppresses cellular but not viral transcription by RNA polymerase II (Pol II), effectively magnifying the depletion of the cellular mRNA pool. We previously showed that transcriptional repression requires the nuclear influx of a pool of cytoplasmic RNA binding proteins, which is triggered by mRNA. Thus, SOX profoundly alters both cellular RNA stability and synthesis and serves as a model for understanding how pathogenic stress impacts transcription. In Aim 2, we will define the sub-nuclear changes that underlie transcriptional repression during lytic KSHV infection, including how specific RNA binding proteins that are relocalized upon mRNA decay contribute mechanistically to this phenotype. Findings derived from this proposal should have a sustained impact on the field of gammaherpesvirus biology and reveal how stress or virus-induced alterations to mRNA stability influence seemingly distal components of the gene regulation circuitry.