Viral RNA Decay
We believe that the cellular mRNA decay machinery can act as an antiviral defense mechanism. After all, many viral RNAs have evolved to mimic cellular transcripts and should therefore be ideal targets for degradation. A degraded genome cannot be replicated or translated, and therefore presents no threat (Dickson and Wilusz, 2011; Moon, Barnhart and Wilusz, 2012). Several projects in the lab focus on characterizing the interactions between viral RNAs and cellular mRNA decay factors. One virus we have investigated extensively is the alphavirus Sindbis Virus (SINV). We have discovered that SINV RNAs are actually quite resistant to decay, and this is likely because they usurp cellular RNA-binding proteins that act as stabilizing factors (Garneau et al 2008, Sokoloski et al, 2010). Our recent results show that many alphaviruses induce relocalization of the cellular HuR protein from the nucleus to the cytoplasm which presumably interferes with its normal functions (Dickson et al, 2012). We have also shown that the rabies virus glycoprotein mRNA can interact with a poly(C) binding protein to enhance its stability (Palusa et al, 2012).
Interestingly, another family of arboviruses, the flaviviruses, have evolved a completely different mechanism of interfering with mRNA decay. When their RNAs are degraded, they generate a stable intermediate called sfRNA, which inhibits the function of the host 5’-3’ exonuclease, XRN1. This results in stabilization of host cell mRNAs and likely has wide-ranging effects on host cell gene expression (Moon et al, 2012). It may also help the viral genomic RNA persist in the host cell cytoplasm.
We hypothesize that other RNA viruses (e.g. Dengue, Rabies, Ebola) will have evolved similar, or novel mechanisms to protect their genomes from the mRNA decay machinery. Moreover, by interfering with these interactions we should be able to induce viral RNA decay and prevent infection.
Moon SL, Anderson JR, Kumagai Y, Wilusz CJ, Akira S, Khromykh AA, Wilusz J. A noncoding RNA produced by arthropod-borne flaviviruses inhibits the cellular exoribonuclease XRN1 and alters host mRNA stability. RNA. 2012 Epub ahead of print.
Dickson AM, Anderson JR, Barnhart MD, Sokoloski KJ, Oko L, Opyrchal M, Galanis E, Wilusz CJ, Morrison TE, Wilusz J. Dephosphorylation of HuR Protein During Alphavirus Infection Is Associated with HuR Relocalization to the Cytoplasm. J Biol Chem. 2012 Aug 22.
Palusa S, Ndaluka C, Bowen RA, Wilusz CJ, Wilusz J. The 3' Untranslated Region of the Rabies Virus Glycoprotein mRNA Specifically Interacts with Cellular PCBP2 Protein and Promotes Transcript Stability. PLoS One. 2012;7(3):e33561.Dickson AM, Wilusz J. Strategies for viral RNA stability: live long and prosper. Trends Genet. 2011 Jul;27(7):286-93.
Sokoloski K.J., Dickson, A.M., 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. Cell Host Microbe. 8(2):196-207
Garneau N.L., Sokoloski K.J., Opyrchal M., Neff C.P., Wilusz C.J. and Wilusz J. (2008) The 3' untranslated region of Sindbis virus represses deadenylation of viral transcripts in mosquito and mammalian cells. J Virol. 82:880-92
Opyrchal M., Anderson J.R., Sokoloski K.J., Wilusz C.J. and Wilusz J. (2005) A cell-free mRNA stability assay reveals conservation of the enzymes and mechanisms of mRNA decay between mosquito and mammalian cell lines. Insect Biochem Mol Biol. 35:1321-34.
Other Labs working on Viral RNA Decay
Karen Beemon - Rous Sarcoma Virus - Johns Hopkins University