Dampening of ISGylation of RIG-I by ADAP regulates type I interferon response of macrophages to RNA virus infection.

While macrophage is one of the major type I interferon (IFN-I) producers in multiple tissues during viral infections, it also serves as an important target cell for many RNA viruses. However, the regulatory mechanism for the IFN-I response of macrophages to respond to a viral challenge is not fully understood. Here we report ADAP, an immune adaptor protein, is indispensable for the induction of the IFN-I response of macrophages to RNA virus infections via an inhibition of the conjugation of ubiquitin-like ISG15 (ISGylation) to RIG-I. Loss of ADAP increases RNA virus replication in macrophages, accompanied with a decrease in LPS-induced IFN-β and ISG15 mRNA expression and an impairment in the RNA virus-induced phosphorylation of IRF3 and TBK1. Moreover, using Adap-/- mice, we show ADAP deficiency strongly increases the susceptibility of macrophages to RNA-virus infection in vivo. Mechanically, ADAP selectively interacts and functionally cooperates with RIG-I but not MDA5 in the activation of IFN-β transcription. Loss of ADAP results in an enhancement of ISGylation of RIG-I, whereas overexpression of ADAP exhibits the opposite effect in vitro, indicating ADAP is detrimental to the RNA virus-induced ISGylation of RIG-I. Together, our data demonstrate a novel antagonistic activity of ADAP in the cell-intrinsic control of RIG-I ISGylation, which is indispensable for initiating and sustaining the IFN-I response of macrophages to RNA virus infections and replication. Author summary: Macrophages are the major type I interferons (IFNs-I) producers upon virus infections, but they are also important target cells for many RNA viruses. Understanding how the IFN-I response of macrophages to RNA virus infection and replication is vital for the development of targeted therapies to mitigate severe viral diseases. To this end, the present study portrays a novel regulatory mechanism whereby ADAP exhibits a virus-suppressive function via dampening of RIG-I ISGylation in the induction of the IFN-I response of macrophages to RNA virus infections. Loss of ADAP dampens RIG-I-type I IFN signaling and renders macrophages more susceptible to virus infection. Therefore, this study provides a new insight into how the permissiveness of macrophages to RNA viruses can be controlled. Additionally, ADAP-RIG-I module can potentially serve as a novel target for therapeutic intervention against diseases caused by RNA viruses. [ABSTRACT FROM AUTHOR]