SFPQ prevents MDA5-mediated activation of innate immunity and preserves cell viability

The melanoma differentiation-associated gene 5 (MDA5) sensor recognizes double-stranded RNA (dsRNA) produced during viral infections, leading to type I interferon (IFN) production. Host proteins can shield endogenous dsRNA from MDA5 through RNA modifications, such as A-to-I editing of dsRNA by adenosine deaminase acting on RNA 1 (ADAR1). The splicing factor proline- and glutamine-rich (SFPQ) is an RNA-binding protein that regulates RNA biogenesis. However, its role in innate immunity has not been previously explored. We report that SFPQ can promote viral replication of Kaposi's sarcoma-associated herpesvirus (KSHV) and demonstrate that SFPQ can prevent IFN production not only in the context of viral replication but also in uninfected cells. Furthermore, SFPQ associates with ADAR1 and modulates A-to-I editing of cellular RNA transcripts. Moreover, SFPQ depletion in uninfected cells induced IFN response genes, including MDA5 and ZBP1, and impaired cell growth. In summary, SFPQ binds ADAR1 and modulates its editing function, thereby preventing cellular RNAs from activating MDA5-mediated innate immune responses.