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PMID: 19587049 Published · ppublish English Journal Article Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov't

Host shutoff is a conserved phenotype of gammaherpesvirus infection and is orchestrated exclusively from the cytoplasm.

Journal of virology ·Vol. 83 ·No. 18 ·2009-09-00 ·Pages 9554-66

Covarrubias S, Richner JM, Clyde K, Lee YJ, Glaunsinger BA

Abstract

Lytic infection with the two human gammaherpesviruses, Kaposi's sarcoma-associated herpesvirus (KSHV) and Epstein-Barr virus (EBV), leads to significant depletion of the cellular transcriptome. This host shutoff phenotype is driven by the conserved herpesviral alkaline exonuclease, termed SOX in KSHV and BGLF5 in EBV, which in gammaherpesviruses has evolved the genetically separable ability to target cellular mRNA. We now show that host shutoff is also a prominent consequence of murine gammaherpesvirus 68 (MHV68) infection, which is widely used as a model system to study pathogenesis of these viruses in vivo. The effector of MHV68-induced host shutoff is its SOX homolog, here termed muSOX. There is remarkable functional conservation of muSOX host shutoff activities with those of KSHV SOX, including the recently described ability of SOX to induce mRNA hyperadenylation in the nucleus as well as cause nuclear relocalization of the poly(A) binding protein. SOX and muSOX localize to both the nucleus and cytoplasm of infected cells. Using spatially restricted variants of these proteins, we go on to demonstrate that all known host shutoff-related activities of SOX and muSOX are orchestrated exclusively from the cytoplasm. These results have important mechanistic implications for how SOX and muSOX target nascent cellular transcripts in the nucleus. Furthermore, our findings establish MHV68 as a new, genetically tractable model to study host shutoff.

MeSH Terms
Animals Cytoplasm/virology Deoxyribonucleases/physiology Gammaherpesvirinae/enzymology,pathogenicity Herpesviridae Infections/virology Herpesvirus 4, Human Herpesvirus 8, Human Host-Pathogen Interactions Humans Mice RNA, Messenger/metabolism Rhadinovirus/pathogenicity Tumor Virus Infections Viral Proteins/physiology
Chemicals
RNA, Messenger Viral Proteins Deoxyribonucleases deoxyribonuclease, Epstein-Barr virus
Authors & Affiliations
5 authors, click to expand affiliations / ORCID
Covarrubias Sergio
University of California, Berkeley, 94720-3102, USA.
Richner Justin M
Clyde Karen
Lee Yeon J
Glaunsinger Britt A
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Article Info
Journal
Journal of virology
Abbr.
J Virol
ISSN
1098-5514
DOI
10.1128/JVI.01051-09
Published
2009-09-00
Epub
2009-00-08
Pages
9554-66
Language
English
Region
United States
NLM ID
0113724
PMCID
PMC2738246
Subset
IM
Grants
NCI NIH HHS · K01 CA117982 · United States
NCI NIH HHS · K01 CA117982-05 · United States
NCI NIH HHS · R01 CA136367 · United States
NCI NIH HHS · 5K01CA117982 · United States
External Links
PubMed source DOI: 10.1128/JVI.01051-09 PMC Full Text View journal details
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