Biochemistry Seminar

Dr. Jeffrey Wilusz
Professor
Colorado State University
Department of Microbiology, Immunology & Pathology

“How Viral RNAs Escape the Wrath of the Cellular RNA Decay Machinery during Infection”

The mechanisms utilized by viruses to protect their transcripts from the cellular RNA decay machinery, as well as the biological relevance of this protection, are largely unexplored.  We have found that Sindbis virus, and likely other alphaviruses, use U-rich 3’ UTR sequences in their capped and polyadenylated RNAs to recruit the cellular HuR protein during infections of both human and mosquito cells.   HuR binds viral RNAs with high specificity and affinity.  Furthermore, Sindbis virus induces the selective movement of HuR protein out of the nucleus of mammalian cells during infection thereby increasing the cytoplasmic pool of the protein available to the virus.  Finally, knockdown of HuR results in a significant increase in the rate of decay of Sindbis virus RNAs and diminishes viral yields in both human and mosquito cells.  Collectively these data indicate that Sindbis virus, and likely other alphaviruses, usurp the HuR protein to avoid the cellular mRNA decay machinery and maintain a highly productive infection.

We have also explored the relationship between the cellular mRNA decay machinery and two other RNA viruses.  Our results suggest that non-polyadenylated flavivirus RNAs may repress the major 5’-3’ pathway of cellular mRNA decay during infections via a direct inhibition of the XRN1 5’-3’ exoribonuclease, perhaps contributing to viral pathogenesis.  Data on Rabies virus, a negative sense RNA virus, suggest that the relative stability of its mRNAs, in addition to the previously described efficiency of transcription via start-stop polymerase initiation, may play an important role in regulating the level of select viral mRNAs during infection.

References

Bergman, N, Moraes KCM, Anderson, J.R., Zaric, B., Kambach, C, Schneider, R.J., Wilusz, C.J. and Wilusz J.  (2007)  Lsm proteins bind to and stabilize RNAs containing 5’ poly(A) tracts.  Nature Struct Mol. Biol.,  14: 824-831.

Garneau, N.L., Sokoloski, K, Opyrchal, M, Neff, C.P., Wilusz, C.J. and Wilusz, J.  (2008).  The 3’ untranslated region of sindbis virus represses the deadenylation of viral transcripts in mosquito and mammalian cells.  J. Virol. 82:  880-892.

Sokoloski, K, Dickson, A, Chaskey E.L., Garneau, N.L., Wilusz, C.J. and Wilusz, J.  (2010).  Sindbis virus usurps the cellular HuR protein to stabilize its transcripts and promote productive infections in mammalian and mosquito cells.  In Revision