Mechanism of transmissible gastroenteritis virus nsp1-mediated translation inhibition
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The non-structural protein 1 (nsp1) proteins of several coronaviruses share a common property to inhibit host gene expression, but use different mechanisms to exert this function. Unlike the nsp1 protein of SARS coronavirus, a group 2b betacoronavirus, the nsp1 protein of transmissible gastroenteritis virus (TGEV), an alphacoronavirus, inhibits the expression of host genes without associating with the 40S ribosomal subunit or inducing the endonucleolytic cleavage of mRNAs. Nsp1 of TGEV strongly inhibits the translation of capped mRNAs, as well as certain internal ribosome entry site (IRES)- containing mRNAs, in HeLa S10 extract but not in rabbit reticulocyte lysate or wheat germ extract. In this dissertation the mechanism of TGEV nsp1-mediated translation inhibition is further elucidated. Immunofluorescence analysis showed that TGEV nsp1 protein localizes to both the nucleus and cytoplasm of expressed cells. TGEV nsp1 can enter the nucleus via passive diffusion because its molecular weight (~9 kDa) is below the passive diffusion exclusion limit of the nuclear pore complex. Both TGEV infection and TGEV nsp1 protein expression inhibit cellular protein synthesis. TGEV nsp1 expression strongly inhibits the expression of reporter genes from transfected reporter plasmids. However, it fails to inhibit the translation of exogenous reporter mRNAs directly introduced into the cytoplasm. These data, along with other findings discussed in this dissertation suggest that TGEV nsp1 uses one or more factors associated with mRNA-protein complexes that originate in the cell nucleus to inhibit mRNA translation.