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Proteolytic Cleavage of Host Proteins by the Group IV Viral Proteases of Venezuelan Equine Encephalitis Virus and Zika Virus

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Journal Article - Open Access

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The alphaviral nonstructural protein 2 nsP2 cysteine proteases EC 3.4.22.- are essential for the proteolytic processing of the nonstructural ns polyprotein and are validated drug targets. A common secondary role of these proteases is to antagonize the effects of interferon IFN. After delineating the cleavage site motif of the Venezuelan equine encephalitis virus VEEV nsP2 cysteine protease, we searched the human genome to identify host protein substrates. Here we identify a new host substrate of the VEEV nsP2 protease, human TRIM14, a component of the mitochondria antiviral-signaling protein MAVS signalosome. Short stretches of homologous host-pathogen protein sequences SSHHPS are present in the nonstructural polyprotein and TRIM14. A 25-residue cyan-yellow fluorescent protein TRIM14 substrate was cleaved in vitro by the VEEV nsP2 protease and the cleavage site was confirmed by tandem mass spectrometry. A TRIM14 cleavage product also was found in VEEV-infected cell lysates. At least ten other Group IV ssRNA viral proteases have been shown to cleave host proteins involved in generating the innate immune responses against viruses, suggesting that the integration of these short host protein sequences into the viral protease cleavage sites may represent an embedded mechanism of IFN antagonism. This interference mechanism shows several parallels with those of CRISPRCas9 and RNAiRISC, but with a protease recognizing a protein sequence common to both the host and pathogen. The short host sequences embedded within the viral genome appear to be analogous to the short phage sequences found in a hosts CRISPR spacer sequences. To test this algorithm, we applied it to another Group IV virus, Zika virus ZIKV, and identified cleavage sites within human SFRP1 secreted frizzled related protein 1, a retinal G, alpha subunit, NT5M, and Forkhead box protein G1 FOXG1 in vitro.

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  • Medicine and Medical Research
  • Biochemistry
  • Microbiology

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