A SAP30 Complex Inhibits IFN-β Expression in Rift Valley Fever Virus Infected Cells

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Abstract
Rift Valley fever virus (RVFV) nonstructural protein NSs acts as the major determinant of virulence by antagonizing interferon β (IFN-β) gene expression. We demonstrate here that NSs interacts with the host protein SAP30, which belongs to Sin3A/NCoR/HDACs repressor complexes and interacts with the transcription factor YY1 that regulates IFN-β gene expression. Using confocal microscopy and chromatin immunoprecipitation, we show that SAP30, YY1, and Sin3A-associated corepressor factors strongly colocalize with nuclear NSs filaments and that NSs, SAP30 and Sin3A-associated factors are recruited on the IFN-β promoter through YY1, inhibiting CBP recruitment, histone acetylation, and transcriptional activation. To ascertain the role of SAP30, we produced, by reverse genetics, a recombinant RVFV in which the interacting domain in NSs was deleted. The virus was unable to inhibit the IFN response and was avirulent for mice. We discuss here the strategy developed by the highly pathogenic RVFV to evade the host antiviral response, affecting nuclear organization and IFN-β promoter chromatin structure. Rift Valley fever is a viral mosquito-borne disease affecting ruminants and humans. The disease occurs in Africa and recently it spread to the Arabian Peninsula. In humans, infection can progress to fatal hemorrhagic fever and in ruminants it leads to hepatitis, abortions, or deaths of young lambs. It has been previously shown that the RVFV protein NSs is the major factor of virulence and that pathogenicity is associated with the lack of interferon production. In this study, we analyzed the interaction of NSs with SAP30, a subunit of complexes intervening in gene transcription regulation. We show that SAP30 through its binding to NSs on one hand and to YY1 (the activator/repressor of interferon transcription) on the other hand, forms a multiprotein repression complex on the interferon β promoter. As a consequence, interferon expression is blocked, allowing virus to invade the whole organism. The relevance of the NSs–SAP30 interaction was ascertained by constructing a recombinant virus in which the interacting domain is disrupted. This virus is able to induce interferon expression and when inoculated to the mouse model it was found nonpathogenic.