Abstract
Retinoic acid-inducible gene I (RIG-I) recognizes RNA virus-derived nucleic acids, which leads to the production of type I interferon (IFN) in most cell types. Tight regulation of RIG-I activity is important to prevent ultra-immune responses. In this study, we identified an ARF-like (ARL) family member, ARL16, as a protein that interacts with RIG-I. Overexpression of ARL16, but not its homologous proteins ARL1 and ARF1, inhibited RIG-I-mediated downstream signaling and antiviral activity. Knockdown of endogenous ARL16 by RNAi potentiated Sendai virus-induced IFN-β expression and vesicular stomatitis virus replication. ARL16 interacted with the C-terminal domain (CTD) of RIG-I to suppress the association between RIG-I and RNA. ARL16 (T37N) and ARL16Δ45-54, which were restricted to the GTP-disassociated form, did not interact with RIG-I and also lost the inhibitory function. Furthermore, we suggest that endogenous ARL16 changes to GTP binding status upon viral infection and binds with the RIG-I CTD to negatively control its signaling activity. These findings suggested a novel innate immune function for an ARL family member, and a GTP-dependent model in which RIG-I is regulated.