# Regulation of mRNA export during gammaherpesvirus infection

> **NIH NIH R01** · UNIVERSITY OF CALIFORNIA LOS ANGELES · 2021 · $440,166

## Abstract

PROJECT SUMMARY
Kaposi sarcoma-associated herpesvirus (KSHV) or human herpesvirus-8 (HHV-8), belongs to the gamma
subfamily of human herpesviruses and is responsible for several human malignancies developed in individuals
infected with human immunodeficiency virus-1 (HIV-1) or AIDS patients. While the incidence of KSHV diseases
has significantly declined since the introduction of highly active antiretroviral therapy (HARRT), Kaposi Sarcoma
(KS) remains to be the major type of cancer worldwide in people living with HIV and AIDS. KSHV is primarily
transmitted through saliva in endemic regions and frequently results in the development of KS in the oral cavity
of AIDS patients.
Like all viruses, the ability of KSHV to manipulate host gene expression is vital for its survival. Recently we
discovered a novel post-transcriptional mechanism encoded by KSHV to accomplish this. KSHV open reading
frame 10 (ORF10) inhibits nuclear export of cellular mRNAs without affecting its own transcripts. This export
inhibitory function of ORF10 requires the interaction with an RNA export factor, Rae1. Furthermore, we showed
that export inhibition of ORF10 is selective for a subset of mRNAs, and that the 3' untranslated regions of the
targeted genes confer transcript sensitivity to ORF10-mediated export inhibition. ORF10 of a closely related
rodent virus, murine gammaherpesvirus 68 (MHV-68), also interacts with Rae1 and is responsible for inhibiting
nuclear export of mRNA during MHV-68 infection. The conservation of protein interaction and protein function
not only underscores the importance of regulating RNA export during gammaherpesvirus infection, but also
argues for MHV-68 as an in vivo model to study ORF10. In this proposal, we will elucidate the molecular
mechanisms of ORF10-mediated selective RNA export inhibition. The result may reveal a novel cellular
regulation of mRNA export. Furthermore, we will determine the functional significance of ORF10 mRNA export
inhibition during gammaherpesvirus infection. We will employ the KSHV and MHV-68 ORF10 mutants to identify
ORF10-specific changes on host gene expression in the context of infection. Finally, we will define the in vivo
role of ORF10 with mouse infection of the MHV-68 ORF10 mutant.
These experiments will increase our understanding of how gammaherpesviruses hijack cellular mRNA export
pathway to facilitate their own replication. Moreover, the study may uncover cellular functions critical for KSHV
replication and provide insights into new therapeutic strategies for KSHV-associated diseases.

## Key facts

- **NIH application ID:** 10107671
- **Project number:** 5R01DE028774-03
- **Recipient organization:** UNIVERSITY OF CALIFORNIA LOS ANGELES
- **Principal Investigator:** TING-TING WU
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $440,166
- **Award type:** 5
- **Project period:** 2019-03-01 → 2024-02-29

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10107671

## Citation

> US National Institutes of Health, RePORTER application 10107671, Regulation of mRNA export during gammaherpesvirus infection (5R01DE028774-03). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10107671. Licensed CC0.

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