MicroRNA-200c-targeted contactin 1 facilitates the replication of influenza A virus by accelerating the degradation of MAVS

Abstract

Influenza A viruses (IAVs) continuously challenge the poultry industry and human health. Elucidation of the host factors that modulate the IAV lifecycle is vital for developing antiviral drugs and vaccines. In this study, we infected A549 cells with IAVs and found that host protein contactin-1 (CNTN1), a member of the immunoglobulin superfamily, enhanced viral replication. Bioinformatic prediction and experimental validation indicated that the expression of CNTN1 was reduced by microRNA-200c (miR-200c) through directly targeting. We further showed that CNTN1-modulated viral replication in A549 cells is dependent on type I interferon signaling. Co-immunoprecipitation experiments revealed that CNTN1 specifically interacts with MAVS and promotes its proteasomal degradation by removing its K63-linked ubiquitination. Moreover, we discovered that the deubiquitinase USP25 is recruited by CNTN1 to catalyze the deubiquitination of K63-linked MAVS. Consequently, the CNTN1-induced degradation cascade of MAVS blocked RIG-I-MAVS-mediated interferon signaling, leading to enhanced viral replication. Taken together, our data reveal novel roles of CNTN1 in the type I interferon pathway and regulatory mechanism of IAV replication. Author summary Type I interferon is an essential component of host immunity against influenza A virus infection. However, the regulatory mechanisms involved in the IAV-induced type I interferon pathway are not fully elucidated. Here, we identified CNTN1 as a critical host factor for the replication of IAV. CNTN1 promotes viral replication by negatively regulating the RIG-I-mediated type I interferon pathway. Mechanistically, CNTN1 specifically enhances the proteasomal degradation of MAVS by promoting USP25-mediated deubiquitination. Our findings uncover novel roles of the host protein CNTN1 in type I interferon signaling and IAV replication.