title: Middle East Respiratory Syndrome Coronavirus nsp1 Inhibits Host Gene Expression by Selectively Targeting mRNAs Transcribed in the Nucleus while Sparing mRNAs of Cytoplasmic Origin.
abstract: The newly emerged Middle East respiratory syndrome coronavirus (MERS-CoV) and severe acute respiratory syndrome CoV (SARS-CoV) represent highly pathogenic human CoVs that share a property to inhibit host gene expression at the posttranscriptional level. Similar to the nonstructural protein 1 (nsp1) of SARS-CoV that inhibits host gene expression at the translational level, we report that MERS-CoV nsp1 also exhibits a conserved function to negatively regulate host gene expression by inhibiting host mRNA translation and inducing the degradation of host mRNAs. Furthermore, like SARS-CoV nsp1, the mRNA degradation activity of MERS-CoV nsp1, most probably triggered by its ability to induce an endonucleolytic RNA cleavage, was separable from its translation inhibitory function. Despite these functional similarities, MERS-CoV nsp1 used a strikingly different strategy that selectively targeted translationally competent host mRNAs for inhibition. While SARS-CoV nsp1 is localized exclusively in the cytoplasm and binds to the 40S ribosomal subunit to gain access to translating mRNAs, MERS-CoV nsp1 was distributed in both the nucleus and the cytoplasm and did not bind stably to the 40S subunit, suggesting a distinctly different mode of targeting translating mRNAs. Interestingly, consistent with this notion, MERS-CoV nsp1 selectively targeted mRNAs, which are transcribed in the nucleus and transported to the cytoplasm, for translation inhibition and mRNA degradation but spared exogenous mRNAs introduced directly into the cytoplasm or virus-like mRNAs that originate in the cytoplasm. Collectively, these data point toward a novel viral strategy wherein the cytoplasmic origin of MERS-CoV mRNAs facilitates their escape from the inhibitory effects of MERS-CoV nsp1.
  
  
  OBJECTIVE
  Middle East respiratory syndrome coronavirus (MERS-CoV) is a highly pathogenic human CoV that emerged in Saudi Arabia in 2012. MERS-CoV has a zoonotic origin and poses a major threat to public health. However, little is known about the viral factors contributing to the high virulence of MERS-CoV. Many animal viruses, including CoVs, encode proteins that interfere with host gene expression, including those involved in antiviral immune responses, and these viral proteins are often major virulence factors. The nonstructural protein 1 (nsp1) of CoVs is one such protein that inhibits host gene expression and is a major virulence factor. This study presents evidence for a strategy used by MERS-CoV nsp1 to inhibit host gene expression that has not been described previously for any viral protein. The present study represents a meaningful step toward a better understanding of the factors and molecular mechanisms governing the virulence and pathogenesis of MERS-CoV.
authors: Department of Microbiology and Immunology, The University of Texas Medical Branch, Galveston, Texas, USA.
authors: Kumari G
authors: KG
authors: Lokugamage
authors: Department of Microbiology and Immunology, The University of Texas Medical Branch, Galveston, Texas, USA.
authors: Krishna
authors: K
authors: Narayanan
authors: Department of Microbiology and Immunology, The University of Texas Medical Branch, Galveston, Texas, USA.
authors: Keisuke
authors: K
authors: Nakagawa
authors: Department of Microbiology and Immunology, The University of Texas Medical Branch, Galveston, Texas, USA.
authors: Kaori
authors: K
authors: Terasaki
authors: Department of Pathology, The University of Texas Medical Branch, Galveston, Texas, USA.
authors: Sydney I
authors: SI
authors: Ramirez
authors: Department of Microbiology and Immunology, The University of Texas Medical Branch, Galveston, Texas, USA Center for Biodefense and Emerging Infectious Diseases, The University of Texas Medical Branch, Galveston, Texas, USA UTMB Center for Tropical Diseases, The University of Texas Medical Branch, Galveston, Texas, USA Sealy Center for Vaccine Development, The University of Texas Medical Branch, Galveston, Texas, USA Institute for Human Infections and Immunity, The University of Texas Medical Branch, Galveston, Texas, USA.
authors: Chien-Te K
authors: CT
authors: Tseng
authors: Department of Microbiology and Immunology, The University of Texas Medical Branch, Galveston, Texas, USA Center for Biodefense and Emerging Infectious Diseases, The University of Texas Medical Branch, Galveston, Texas, USA UTMB Center for Tropical Diseases, The University of Texas Medical Branch, Galveston, Texas, USA Sealy Center for Vaccine Development, The University of Texas Medical Branch, Galveston, Texas, USA Institute for Human Infections and Immunity, The University of Texas Medical Branch, Galveston, Texas, USA shmakino@utmb.edu.
authors: Shinji
authors: S
authors: Makino
mesh_terms: D015152:Blotting, Northern; D015153:Blotting, Western; D002467:Cell Nucleus / Q000378:metabolism*; D003593:Cytoplasm / Q000378:metabolism; D017931:DNA Primers; D018819:Dipeptidyl Peptidase 4 / Q000378:metabolism; D018274:Electroporation; D005786:Gene Expression Regulation / Q000235:genetics*; D057809:HEK293 Cells; D006801:Humans; D018613:Microscopy, Confocal; D065207:Middle East Respiratory Syndrome Coronavirus / Q000235:genetics* / Q000378:metabolism; D010957:Plasmids / Q000235:genetics; D012333:RNA, Messenger / Q000378:metabolism*; D060888:Real-Time Polymerase Chain Reaction; D020133:Reverse Transcriptase Polymerase Chain Reaction; D017361:Viral Nonstructural Proteins / Q000378:metabolism*
chemical_list: D017931:DNA Primers; D012333:RNA, Messenger; D017361:Viral Nonstructural Proteins; C042807:DPP4 protein, human; D018819:Dipeptidyl Peptidase 4