Editors' ChoiceInnate Immunity

Viral sensors get more involved

Sci. Signal.  19 May 2015:
Vol. 8, Issue 377, pp. ec130
DOI: 10.1126/scisignal.aac5842

The DExD/H helicases RIG-I and MDA5 are cytosolic pattern-recognition receptors (PRRs) that bind to different forms of viral double-stranded RNA (dsRNA), oligomerize, and activate transcription factors required for the expression of genes encoding type I interferons (IFNs). Another branch of the antiviral immune response is mediated by “effector” proteins, such as protein kinase R (PKR), which binds to viral dsRNA, undergoes autophosphorylation, and then phosphorylates the translation initiation factor eIF2α to suppress protein synthesis and inhibit viral replication. Viruses produce proteins that bind to dsRNA to block the activities of both PRRs and effector proteins. Yao et al. showed that RIG-I and MDA5 also act like effector proteins. In vitro studies showed that RIG-I and MDA5 displaced the viral blocking proteins NS1 and E3L that were pre-bound to dsRNA. Viral protein displacement required the intrinsic ATPase activity of both PRRs, but not the domains necessary for activation of the type I IFN response. Analysis of the autophosphorylation of PKR in vitro showed that dsRNA-bound viral blocking proteins inhibited PKR activation; however, RIG-I and MDA5 increased PKR activation by removing the viral proteins from the dsRNA. NS1 and E3L were prevented from inhibiting PKR activation in transfected cells expressing the mutants RIG-IΔN or MDA5ΔN, which are devoid of the domains required for induction of type I IFN responses. Both RIG-IΔN and MDA5ΔN suppressed the replication of a panel of viruses used to infect a human cell line; however, this antiviral activity was lost if mutant RIG-I or MDA5 proteins deficient in ATPase activity were expressed in the cells. Together, these data indicate that RIG-I and MDA5 act both as PRRs and effector proteins to enable antiviral immune responses.

H. Yao, M. Dittmann, A. Peisley, H.-H. Hoffmann, R. H. Gilmore, T. Schmidt, J. L. Schmid-Burgk, V. Hornung, C. M. Rice, S. Hur, ATP-dependent effector-like functions of RIG-I–-like receptors. Mol. Cell 58, 541–548 (2015). [PubMed]