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The Levels of Retinoic Acid-Inducible Gene I Are Regulated by Heat Shock Protein 90-¹

Tomoh Matsumiya^*,, Tadaatsu Imaizumi, Hidemi Yoshida, Kei Satoh, Matthew K. Topham^*, and Diana M. Stafforini^2,*,

^* Huntsman Cancer Institute and Department of Internal Medicine, University of Utah, Salt Lake City, UT 84112; and Department of Vascular Biology, Institute of Brain Sciences, Hirosaki University Graduate School of Medicine, Hirosaki City, Japan

Retinoic acid-inducible gene I (RIG-I) is an intracellular pattern recognition receptor that plays important roles during innate immune responses to viral dsRNAs. The mechanisms and signaling molecules that participate in the downstream events that follow activation of RIG-I are incompletely characterized. In addition, the factors that define intracellular availability of RIG-I and determine its steady-state levels are only partially understood but are likely to play a major role during innate immune responses. It was recently reported that the antiviral activity of RIG-I is negatively regulated by specific E3 ubiquitin ligases, suggesting participation of the proteasome in the regulation of RIG-I levels. In this study, we used immunoprecipitation combined with mass spectrometry to identify RIG-I-interacting proteins and found that RIG-I forms part of a protein complex that includes heat shock protein 90- (HSP90-), a molecular chaperone. Biochemical studies using purified systems demonstrated that the association between RIG-I and HSP90- is direct but does not involve participation of the CARD domain. Inhibition of HSP90 activity leads to the dissociation of the RIG-I-HSP90 complex, followed by ubiquitination and proteasomal degradation of RIG-I. In contrast, the levels of RIG-I mRNA are unaffected. Our studies also show that the ability of RIG-I to respond to stimulation with polyinosinic:polycytidylic acid is abolished when its interaction with HSP90 is inhibited. These novel findings point to HSP90- as a chaperone that shields RIG-I from proteasomal degradation and modulates its activity. These studies identify a new mechanism whose dysregulation may seriously compromise innate antiviral responses in mammals.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ This work was supported by the Huntsman Cancer Foundation, by a grant from the National Institutes of Health (P01-CA73992) to D.M.S., and by Cancer Center Support Grant P30 CA042014-20.

² Address correspondence and reprint requests to Dr. Diana M. Stafforini, Huntsman Cancer Institute, 2000 Circle of Hope, Suite 3364, University of Utah, Salt Lake City, UT 84112. E-mail address: diana.stafforini{at}hci.utah.edu

³ Abbreviations used in this paper: RIG-I, retinoic acid-inducible gene I; CARD, caspase recruitment domain; HSP, heat shock protein 70; ISG15, IFN-regulated gene 15; IPS-1, IFN-β promoter stimulator 1; poly(I:C), polyinosinic:polycytidylic acid; HMG-1, high-mobility group protein 1.