Contents - College of Medical and Dental Sciences - University of ...
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The 11 th International Workshop on KSHV & Related Agents, Birmingham, UK<br />
Gene Expression II Abstract 34<br />
ROLE OF MURINE GAMMAHERPESVIRUS-68 ORF37 IN MEDIATING INHIBITION<br />
OF HOST GENE EXPRESSION<br />
L. Roaden 1 , V. Sheridan 1 , B. Lane 1 , R. Sun 2 , B. Dutia 3 <strong>and</strong> B. Ebrahimi 1<br />
1 Division <strong>of</strong> <strong>Medical</strong> Microbiology, School <strong>of</strong> Infection & Host Defence, <strong>University</strong> <strong>of</strong><br />
Liverpool, Liverpool L69 3GA, UK, 2 Molecular Biology Institute, <strong>University</strong> <strong>of</strong> California,<br />
Los Angeles, California, USA, <strong>and</strong> 3 Centre for Infectious Diseases, Division <strong>of</strong> Veterinary<br />
Biomedical <strong>Sciences</strong>, <strong>University</strong> <strong>of</strong> Edinburgh, UK.<br />
Abstract<br />
In lytic infection, Murine gammaherpesvirus-68 (MHV-68) <strong>and</strong> Kaposi’s sarcoma<br />
associated herpesvirus (KSHV) <strong>and</strong> Epstein-Barr virus have been shown to mediate a<br />
global inhibition <strong>of</strong> host gene expression. g-herpesviruses, unlike a-herpesviruses, do<br />
not encode RNases. Recently, however, the KSHV ORF37 (an alkaline DNA exonuclease,<br />
also known as SOX) was shown to promote this shutdown by enhancing the degradation<br />
<strong>of</strong> cellular mRNAs. Similar observations have been made with the EBV homologue <strong>of</strong><br />
SOX. Interestingly, SOX does not appear to possess any apparent RNase activity. The<br />
murine gammaherpesvirus-68 (MHV-68) encodes an ORF37 highly homologous to KSHV<br />
ORF37 both at DNA (55% identity) <strong>and</strong> protein (44% identity) levels. Here we show that<br />
MHV-68 is capable <strong>of</strong> orchestrating a global repression <strong>of</strong> cellular gene expression. Using<br />
transient transfection assays <strong>and</strong> engineered reporters with very rapid half-lives, we<br />
show that ORF37 can independently cause rapid loss <strong>of</strong> these transcripts when expressed<br />
in transient transfection assays. Using point mutations, we have been able to dissect key<br />
amino acids which may relate to the RNase activity <strong>of</strong> MHV-68 ORF37. Furthermore, we<br />
have generated a stop mutant <strong>of</strong> MHV-68 ORF37 to assess the potential shutdown<br />
properties <strong>of</strong> this viral protein during lytic infection in vitro <strong>and</strong> in vivo <strong>and</strong> its potential<br />
role in host gene shut-<strong>of</strong>f during latency <strong>and</strong> reactivation from latency in vivo.<br />
Presenting author Email: ebrahimi@liv.ac.uk<br />
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