Novy, K; Kilcher, S; Omasits, U; Bleck, CKE; Beerli, C; Vowinckel, J; Martin, CK; ... Wollscheid, B; + view all Novy, K; Kilcher, S; Omasits, U; Bleck, CKE; Beerli, C; Vowinckel, J; Martin, CK; Syedbasha, M; Maiolica, A; White, I; Mercer, J; Wollscheid, B; - view fewer (2018) Proteotype profiling unmasks a viral signalling network essential for poxvirus assembly and transcriptional competence. Nature Microbiology , 3 (5) pp. 588-599. 10.1038/s41564-018-0142-6.

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Abstract

To orchestrate context-dependent signalling programmes, poxviruses encode two dual-specificity enzymes, the F10 kinase and the H1 phosphatase. These signalling mediators are essential for poxvirus production, yet their substrate profiles and systems-level functions remain enigmatic. Using a phosphoproteomic screen of cells infected with wild-type, F10 and H1 mutant vaccinia viruses, we systematically defined the viral signalling network controlled by these enzymes. Quantitative cross-comparison revealed 33 F10 and/or H1 phosphosites within 17 viral proteins. Using this proteotype dataset to inform genotype-phenotype relationships, we found that H1-deficient virions harbour a hidden hypercleavage phenotype driven by reversible phosphorylation of the virus protease I7 (S134). Quantitative phosphoproteomic profiling further revealed that the phosphorylation-dependent activity of the viral early transcription factor, A7 (Y367), underlies the transcription-deficient phenotype of H1 mutant virions. Together, these results highlight the utility of combining quantitative proteotype screens with mutant viruses to uncover proteotype-phenotype-genotype relationships that are masked by classical genetic studies.

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