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PLoS One. 2018 Feb 6;13(2):e0191983. doi: 10.1371/journal.pone.0191983. eCollection 2018.

Phosphoproteomic analysis reveals Smad protein family activation following Rift Valley fever virus infection.

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National Center for Biodefense and Infectious Diseases, School of Systems Biology, George Mason University, Manassas, Virginia, United States of America.
United States Army Medical Research Institute of Infectious Diseases, Frederick, Maryland, United States of America.
Center for Applied Proteomics and Molecular Medicine, School of Systems Biology, George Mason University, Manassas, Virginia, United States of America.
DCE Consulting, Vienna, Virginia, United States of America.


Rift Valley fever virus (RVFV) infects both ruminants and humans leading to a wide variance of pathologies dependent on host background and age. Utilizing a targeted reverse phase protein array (RPPA) to define changes in signaling cascades after in vitro infection of human cells with virulent and attenuated RVFV strains, we observed high phosphorylation of Smad transcription factors. This evolutionarily conserved family is phosphorylated by and transduces the activation of TGF-β superfamily receptors. Moreover, we observed that phosphorylation of Smad proteins required active RVFV replication and loss of NSs impaired this activation, further corroborating the RPPA results. Gene promoter analysis of transcripts altered after RVFV infection identified 913 genes that contained a Smad-response element. Functional annotation of these potential Smad-regulated genes clustered in axonal guidance, hepatic fibrosis and cell signaling pathways involved in cellular adhesion/migration, calcium influx, and cytoskeletal reorganization. Furthermore, chromatin immunoprecipitation confirmed the presence of a Smad complex on the interleukin 1 receptor type 2 (IL1R2) promoter, which acts as a decoy receptor for IL-1 activation.

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