The gammaherpesviruses Kaposi's sarcoma-associated herpesvirus (KSHV) and Epstein-Barr virus (EBV) are major causes of cancers in immunocompromised individuals. In the case of KSHV, infection rates in sub-Saharan Africa can approach 80% and, as a result, the incidence there of Kaposi's sarcoma is rising and it is emerging as one of the most common adult malignancies. These large double stranded DNA viruses are amplified during lytic replication, but persist for the lifetime of their host in a nonreplicative, latent state. While tumorigenesis is predominantly associated with the latent form of the virus, for KSHV latency is generally not a transforming event and KSHV-induced diseases also require low-level, ongoing lytic replication. Lytic replication is necessary both as a source of new virus to infect naive cells, and to drive production of viral and host paracrine factors that enhance growth of latently infected cells and create an appropriate tumor microenvironment. However, one prominent phenotype occurring during lytic gammaherpesvirus infection is the widespread destruction of cellular messenger RNA (mRNA), which potently inhibits host gene expression. Thus, there is a paradox between the necessity for lytically infected cells to induce specific host genes and the concomitant block in cellular gene expression. The goal of this project is to determine mechanistically how specific host genes evade destruction. Degradation of mRNA during lytic infection is orchestrated by the viral SOX protein, which coordinates with cellular RNA turnover factors to execute shutoff of gene expression. Interestingly, we have observed that select messages such as interleukin-6 (IL-6) are directly refractory to SOX-induced turnover. In the case of IL-6, we have mapped a cis-acting escape element to a region of its 3'untranslated region, and identified several host proteins that complex with this RNA element. One aspect of the project is therefore to explore the mechanistic consequences of these RNA-protein interactions, and determine how they influence IL-6 mRNA stability in the presence and absence of SOX. Given the numerous roles for IL-6 in human disease, this information will be relevant both to KSHV-induced neoplasms as well as potential dysregulation of this cytokine in other cancers. We will then broaden our focus to explore potentially conserved mechanisms of escape, using genome-wide data sets obtained from microarray and deep sequencing analyses. We anticipate these studies may reveal novel pathways that control message fate, and how manipulation of such pathways contributes to both infectious and genetic diseases.

Public Health Relevance

Human gammaherpesviruses are a major cause of cancers in immunocompromised individuals. In order to cause disease, these viruses drive their infected cells to produce proteins that assist in the growth and survival of neighboring tumor cells. This project aims to determine how these necessary host factors accumulate, even though the majority of other host genes are eliminated by these viruses.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA160556-02
Application #
8309954
Study Section
Virology - A Study Section (VIRA)
Program Officer
Read-Connole, Elizabeth Lee
Project Start
2011-08-01
Project End
2016-05-31
Budget Start
2012-06-01
Budget End
2013-05-31
Support Year
2
Fiscal Year
2012
Total Cost
$311,555
Indirect Cost
$104,055
Name
University of California Berkeley
Department
Other Basic Sciences
Type
Schools of Earth Sciences/Natur
DUNS #
124726725
City
Berkeley
State
CA
Country
United States
Zip Code
94704
Karijolich, John; Abernathy, Emma; Glaunsinger, Britt A (2015) Infection-Induced Retrotransposon-Derived Noncoding RNAs Enhance Herpesviral Gene Expression via the NF-κB Pathway. PLoS Pathog 11:e1005260
Glaunsinger, Britt A (2015) Modulation of the Translational Landscape During Herpesvirus Infection. Annu Rev Virol 2:311-33
Muller, Mandy; Hutin, Stephanie; Marigold, Oliver et al. (2015) A ribonucleoprotein complex protects the interleukin-6 mRNA from degradation by distinct herpesviral endonucleases. PLoS Pathog 11:e1004899
Gaglia, Marta Maria; Rycroft, Chris H; Glaunsinger, Britt A (2015) Transcriptome-Wide Cleavage Site Mapping on Cellular mRNAs Reveals Features Underlying Sequence-Specific Cleavage by the Viral Ribonuclease SOX. PLoS Pathog 11:e1005305
Abernathy, Emma; Glaunsinger, Britt (2015) Emerging roles for RNA degradation in viral replication and antiviral defense. Virology 479-480:600-8
Davis, Zoe H; Verschueren, Erik; Jang, Gwendolyn M et al. (2015) Global mapping of herpesvirus-host protein complexes reveals a transcription strategy for late genes. Mol Cell 57:349-60
Abernathy, Emma; Gilbertson, Sarah; Alla, Ravi et al. (2015) Viral Nucleases Induce an mRNA Degradation-Transcription Feedback Loop in Mammalian Cells. Cell Host Microbe 18:243-53
Ma, Zhe; Jacobs, Sarah R; West, John A et al. (2015) Modulation of the cGAS-STING DNA sensing pathway by gammaherpesviruses. Proc Natl Acad Sci U S A 112:E4306-15
Wong-Ho, Elaine; Wu, Ting-Ting; Davis, Zoe H et al. (2014) Unconventional sequence requirement for viral late gene core promoters of murine gammaherpesvirus 68. J Virol 88:3411-22
Kronstad, Lisa M; Brulois, Kevin F; Jung, Jae U et al. (2014) Reinitiation after translation of two upstream open reading frames (ORF) governs expression of the ORF35-37 Kaposi's sarcoma-associated herpesvirus polycistronic mRNA. J Virol 88:6512-8

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