Editors' ChoiceAntiviral Signaling

Two-for-One Suppression of the Antiviral Response

Science Signaling  22 Jul 2014:
Vol. 7, Issue 335, pp. ec193
DOI: 10.1126/scisignal.2005712

The cytoplasmic RIG-I–like receptors (RLRs) RIG-I and MDA5 are important components of the innate immune response to RNA viruses, such as the measles virus. Constitutive phosphorylation of Ser8 and Thr170 in RIG-I and Ser88 in MDA5 maintains these RLRs in an inactive state in noninfected cells. When these RLRs bind to viral RNAs, the α and γ isoforms of protein phosphatase 1 (PP1α and PP1γ) remove the inhibitory phosphate groups to enable antiviral signaling. Two studies report distinct mechanisms by which the V protein of measles virus (MV-V) suppresses the antiviral response by interfering with PP1-mediated dephosphorylation of RLRs. Using cultured epithelial cells, Davis et al. found that MV-V coimmunoprecipitated with PP1α and PP1γ from extracts of infected cells and colocalized with PP1γ at intracellular sites of MDA5 antiviral signaling. When expressed in transfected cells, MV-V competed with MDA5 for binding to PP1α and PP1γ and reduced dephosphorylation of MDA5 Ser88. Experiments with various phosphatase inhibitors indicated that PP1α dephosphorylated MV-V in cells and purified PP1α dephosphorylated MV-V in vitro. The authors identified the region of MV-V that mediated binding to PP1 and demonstrated that this region was required for inhibiting MDA5 dephosphorylation. Viruses containing a mutant form of MV-V that was unable to bind to PP1 (VΔtail) did not suppress antiviral responses, which resulted in reduced virus replication compared with that of wild-type virus. Dendritic cells (DCs), not epithelial cells, are the in vivo target during the early stages of measles virus infection. MDA5 remained phosphorylated in primary human DCs infected with wild-type measles virus but was dephosphorylated in DCs infected with the VΔtail virus. These results suggest that MV-V interferes with the antiviral response by competing with MDA5 for PP1-mediated dephosphorylation. In a related study, Mesman et al. report that MV-V also suppressed RLR signaling by inhibiting PP1 catalytic activity in primary human DCs. Suppression of the antiviral response in these cells by MV-V required the cell-surface lectin DC-SIGN, and MV-V–mediated activation of DC-SIGN stimulated signaling through the serine-threonine kinase Raf-1. Activation of DC-SIGN by antibody-mediated cross-linking blocked PP1-mediated dephosphorylation of Ser8 and Thr170 in RIG-I and Ser88 in MDA5, and inhibiting Raf-1 prevented this effect. Raf-1 blocked PP1 activity by promoting the association of the PP1 inhibitor I-1 with PP1. Knocking down I-1 or Raf-1 by RNA interference reduced measles virus infection. These results indicate that MV-V inhibits RLR-mediated antiviral responses by stimulating DC-SIGN, leading to Raf-1 activation and inhibition of PP1-mediated activation of RIG-I and MDA5. Commentary by Seya considers the implications of these findings for suppression of the antiviral response in vivo by measles virus and other paramyxoviruses.

M. E. Davis, M. K. Wang, L. J. Rennick, F. Full, S. Gableske, A. W. Mesman, S. I. Gringhuis, T. B. H. Geijtenbeek, W. P. Duprex, M. U. Gack, Antagonism of the phosphatase PP1 by the measles virus V protein is required for innate immune escape of MDA5. Cell Host Microbe 16, 19–30 (2014). [PubMed]

A. W. Mesman, E. M. Zijlstra-Willems, T. M. Kaptein, R. L. de Swart, M. E. Davis, M. Ludlow, W. P. Duprex, M. U. Gack, S. I. Gringhuis, T. B. H. Geijtenbeek, Measles virus suppresses RIG-I-like receptor activation in dendritic cells via DC-SIGN-mediated inhibition of PP1 phosphatases. Cell Host Microbe 16, 31–42 (2014). [PubMed]

T. Seya, Measles virus takes a two-pronged attack on PP1. Cell Host Microbe 16, 1–2 (2014). [PubMed]