A prevailing view is that the HSV-1 UL41 tegument protein mediates nonspecific degradation of both viral and cellular mRNAs by cleavage of the RNA at or near the 5' terminus and that viral gene expression prevails because of a higher rate of transcription of viral genes. Our studies that form the basis of this grant application challenge several aspects of this view. Specifically: (i) Microarray analyses revealed the up regulation of several hundred genes in infected cells as compared to mock-infected cells. Validation studies (Northern analyses, Real-Time PCR and immunoblots) revealed 4 groups of mRNAs. Group 1 exemplified by IEX-1, c-fos, cox-2 and Ikappabalpha mRNAs were indeed up regulated but the protein products were not made. These mRNAs were degraded in a UL41 dependent manner by deadenylation, endonucleolytic cleavage and 3' to 5' processive degradation. Moreover, the 5' domains of the partially degraded mRNAs tended to linger and were readily detected in cytoplasmic extracts. Group 2 exemplified by tristetraprolin (TTP) mRNA and group 3 exemplified by GADD45beta mRNA were also up regulated but were stable and indeed translated, again all in a UL41 dependent manner!! Actin mRNA, abundant but not up regulated was rapidly degraded. The RNAs forming groups 2 and 3 contain A-U rich elements characteristic of rapidly turning over mRNAs whereas actin and GADD45beta mRNAs do not have these elements. TTP is a stress-related protein involved in the degradation of A-U rich mRNAs by binding and translocating these mRNAs to exosomes. In essence, the degradation of mRNA mediated by the UL41 protein is not indiscriminant but highly selective. This application has 4 aims i.e.(1) To identify the sequences in TTP mRNA that confer selective stability to the mRNA in wild-type virus infected cells;.(2) To define the mechanism by which the TTP mRNA is spared from degradation in wild-type virus infected cells.(3) To define the basis for the differential rates of degradation of mRNAs containing A-U rich elements in wild-type virus infected cells as compared to uninfected cells or cells infected with ?UL41 mutant virus, and (4) to determine whether the numerous functions now associated with the UL41 protein are co-variant and the role of these functions in the biology of HSV-1.

National Institute of Health (NIH)
National Cancer Institute (NCI)
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Virology - B Study Section (VIRB)
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Daschner, Phillip J
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University of Chicago
Schools of Medicine
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Shu, Minfeng; Taddeo, Brunella; Roizman, Bernard (2015) Tristetraprolin Recruits the Herpes Simplex Virion Host Shutoff RNase to AU-Rich Elements in Stress Response mRNAs To Enable Their Cleavage. J Virol 89:5643-50
Zhu, Zhi; Du, Te; Zhou, Guoying et al. (2014) The stability of herpes simplex virus 1 ICP0 early after infection is defined by the RING finger and the UL13 protein kinase. J Virol 88:5437-43
Kalamvoki, Maria; Roizman, Bernard (2014) HSV-1 degrades, stabilizes, requires, or is stung by STING depending on ICP0, the US3 protein kinase, and cell derivation. Proc Natl Acad Sci U S A 111:E611-7
Taddeo, Brunella; Zhang, Weiran; Roizman, Bernard (2013) The herpes simplex virus host shutoff RNase degrades cellular and viral mRNAs made before infection but not viral mRNA made after infection. J Virol 87:4516-22
Shu, Minfeng; Taddeo, Brunella; Roizman, Bernard (2013) The nuclear-cytoplasmic shuttling of virion host shutoff RNase is enabled by pUL47 and an embedded nuclear export signal and defines the sites of degradation of AU-rich and stable cellular mRNAs. J Virol 87:13569-78
Shu, Minfeng; Taddeo, Brunella; Zhang, Weiran et al. (2013) Selective degradation of mRNAs by the HSV host shutoff RNase is regulated by the UL47 tegument protein. Proc Natl Acad Sci U S A 110:E1669-75
Sciortino, Maria Teresa; Parisi, Tiziana; Siracusano, Gabriel et al. (2013) The virion host shutoff RNase plays a key role in blocking the activation of protein kinase R in cells infected with herpes simplex virus 1. J Virol 87:3271-6
Taddeo, Brunella; Zhang, Weiran; Roizman, Bernard (2010) Role of herpes simplex virus ICP27 in the degradation of mRNA by virion host shutoff RNase. J Virol 84:10182-90
Taddeo, Brunella; Zhang, Weiran; Roizman, Bernard (2009) The virion-packaged endoribonuclease of herpes simplex virus 1 cleaves mRNA in polyribosomes. Proc Natl Acad Sci U S A 106:12139-44
Smith-Donald, Benjamin A; Durand, Lizette O; Roizman, Bernard (2008) Role of cellular phosphatase cdc25C in herpes simplex virus 1 replication. J Virol 82:4527-32

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