Viral nucleic acids are sensed by pattern recognition receptors, leads to produce of type I IFN to exert antiviral activities. Type I IFN binds to its cognate receptor, IFNAR, resulting in the activation of STAT1. Thus it has long been thought dsRNA-introduced STAT1 phosphorylation is through transactivation of type I IFN signaling. Foreign RNA entered into cell such as viral RNA is sensed by cytoplasmic sensors retinoic acid-inducible gene-I (RIG-I) and melanoma differentiation-associated gene-5 (MDA-5). In this study, we explored the molecular mechanism of how STAT1 phosphorylation is regulated by dsRNA through the cytosolic RNA sensors. A synthetic dsRNA polyinosinic-polycytidylic acid (polyI:C) induces STAT1 phosphorylation. We found the polyI:C-induced initial STAT1 phosphorylation is dependent on RIG-I pathway and MDA-5 is not involved in the STAT1 phosphorylation. Neither the pathway for RIG-I nor type I IFN is involved in the late phosphorylation of STAT1. polyI:C were able to stimulate STAT1 phosphorylation in type I IFN receptor-deficient U5A cells, suggesting this initial phosphorylation is predominantly type I IFN-dependent; however, studies using IFN receptor neutralizing antibody indicated the presence of IFN independent- and RIG-I-dependent pathway for STAT1 activation. Taken together, our results showed comprehensive regulation in which dsRNA induces STAT1 phosphorylation, indicating importance of STAT1 with such a tight regulation in innate immune system.
- Copyright © 2013 by The American Association of Immunologists, Inc.