Nuclear matrix protein Matrin 3 is a regulator of ZAP-mediated retroviral restriction

Background: Matrin 3 is a nuclear matrix protein involved in multiple nuclear processes. In HIV-1 infection, Matrin 3 serves as a Rev cofactor important for the cytoplasmic accumulation of HIV-1 transcripts. ZAP is a potent host restriction factor of multiple viruses including retroviruses HIV-1 and MoMuLV. In this study we sought to further characterize Matrin 3 functions in the regulation of HIV gene expression. Results: Here we describe a function for Matrin 3 as a negative regulator of the ZAP-mediated restriction of retroviruses. Mass spectrometry analysis of Matrin 3-associated proteins uncovered interactions with proteins of the ZAP degradation complex, DDX17 and EXOSC3. Coimmunoprecipitation studies confirmed Matrin 3 associations with DDX17, EXOSC3 and ZAP, in a largely RNA-dependent manner, indicating that RNA is mediating the Matrin 3 interactions with these components of the ZAP degradation complex. Silencing Matrin 3 expression caused a remarkably enhanced ZAP-driven inhibition of HIV-1 and MoMuLV luciferase reporter viruses. This effect was shared with additional nuclear matrix proteins. ZAP targets multiply-spliced HIV-1 transcripts, but in the context of Matrin 3 suppression, this ZAP restriction was broadened to unspliced and multiply-spliced RNAs. Conclusions: Here we reveal an unprecedented role for a nuclear matrix protein, Matrin 3, in the regulation of ZAP's antiretroviral activity. Suppressing Matrin 3 powers a heightened and broader ZAP restriction of HIV-1 gene expression. This study suggests that this ZAP regulatory mechanism is shared with additional nuclear matrix proteins.