DUSP4 regulates STING- and RIG-I-mediated signalling in response to virus infection

Abstract MAPK phosphatase (MKPs), also known as dual-specificity phosphatases (DUSPs), are cysteine-based protein tyrosine phosphatases that dephosphorylate phosphotyrosine, phosphothreonine, and phosphoserine residues in their substrates. They are originally identified as the major negative regulators of MAP kinases (MAPKs). Our recent study on DUSP10/MKP5 demonstrated that this molecule plays an important role in immune response to virus infection via dephosphorylating IRF3. DUSP4/MKP2 is another DUSP/MKP family member whose function in immune response to virus infection is unclear. This study aims to elucidate the regulatory function of DUSP4 in STING- and RIG-I-mediated signaling and in innate immune response to virus infection. We found that this protein is constitutively expressed in immune cells such as macrophages and its expression is increased in response to the activation of RIG-I and STING as well as virus infection including influenza and HSV. Studies using cells and mice deficient in DUSP4/MKP2 demonstrate that this molecule inhibits STING- and RIG-I-mediated signaling, thereby inhibiting the expression of proinflammatory cytokines including IL-6 and TNFa as well as type I interferon such as IFNb. Furthermore, DUSP4 deficient mice developed less severe diseases upon influenza and HSV infection, but more severe disease upon malaria parasite infection. Our studies demonstrate a novel function of DUSP4 in immune response to microbial infection and may be further explored for therapeutic purposes.