title: RIG-I-Mediated STING Upregulation Restricts Herpes Simplex Virus 1 Infection.
abstract: STING has emerged in recent years as a key player in orchestrating innate immune responses to cytosolic DNA and RNA derived from pathogens. However, the regulation of STING still remains poorly defined. In the present study, we investigated the mechanism of the regulation of STING expression in relation to the RIG-I pathway. Our data show that signaling through RIG-I induces STING expression at both the transcriptional and protein levels in various cell types. STING induction by the RIG-I agonist 5'triphosphorylated RNA (5'pppRNA) was recognized to be a delayed event resulting from an autocrine/paracrine mechanism. Indeed, cotreatment with tumor necrosis factor alpha and type I/II interferon was found to have a synergistic effect on the regulation of STING expression and could be potently decreased by impairing NF-κB and/or STAT1/2 signaling. STING induction significantly contributed to sustainment of the immune signaling cascade following 5'pppRNA treatment. Physiologically, this cross talk between the RNA- and DNA-sensing pathways allowed 5'pppRNA to efficiently block infection by herpes simplex virus 1 (HSV-1) both in vitro and in vivo in a STING-dependent fashion. These observations demonstrate that STING induction by RIG-I signaling through the NF-κB and STAT1/2 cascades is essential for RIG-I agonist-mediated HSV-1 restriction.
  
  
  
  The innate immune system represents the first line of defense against invading pathogens. The dysregulation of this system can result in failure to combat pathogens, inflammation, and autoimmune diseases. Thus, precise regulation at each level of the innate immune system is crucial. Recently, a number of studies have established STING to be a central molecule in the innate immune response to cytosolic DNA and RNA derived from pathogens. Here, we describe the regulation of STING via RIG-I-mediated innate immune sensing. We found that STING is synergistically induced via proinflammatory and antiviral cytokine cascades. In addition, we show that in vivo protection against herpes simplex virus 1 (HSV-1) by a RIG-I agonist required STING. Our study provides new insights into the cross talk between DNA and RNA pathogen-sensing systems via the control of STING.
authors: Lady Davis Institute-Jewish General Hospital, McGill University, Montreal, Quebec, Canada Division of Experimental Medicine, McGill University, Montreal, Quebec, Canada.
authors: Yiliu
authors: Y
authors: Liu
authors: Lady Davis Institute-Jewish General Hospital, McGill University, Montreal, Quebec, Canada.
authors: Marie-Line
authors: ML
authors: Goulet
authors: Lady Davis Institute-Jewish General Hospital, McGill University, Montreal, Quebec, Canada Division of Experimental Medicine, McGill University, Montreal, Quebec, Canada.
authors: Alexandre
authors: A
authors: Sze
authors: Lady Davis Institute-Jewish General Hospital, McGill University, Montreal, Quebec, Canada.
authors: Samar Bel
authors: SB
authors: Hadj
authors: Lady Davis Institute-Jewish General Hospital, McGill University, Montreal, Quebec, Canada.
authors: Sidi Mehdi
authors: SM
authors: Belgnaoui
authors: Lady Davis Institute-Jewish General Hospital, McGill University, Montreal, Quebec, Canada Department of Microbiology & Immunology, McGill University, Montreal, Quebec, Canada.
authors: Rassin R
authors: RR
authors: Lababidi
authors: Institutes of Biology and Medical Sciences, Soochow University, Suzhou, China.
authors: Chunfu
authors: C
authors: Zheng
authors: Department of Microbiology & Immunology, McGill University, Montreal, Quebec, Canada.
authors: Jörg Hermann
authors: JH
authors: Fritz
authors: Lady Davis Institute-Jewish General Hospital, McGill University, Montreal, Quebec, Canada Division of Experimental Medicine, McGill University, Montreal, Quebec, Canada david.olagnier@mail.mcgill.ca rongtuan.lin@mcgill.ca.
authors: David
authors: D
authors: Olagnier
authors: Lady Davis Institute-Jewish General Hospital, McGill University, Montreal, Quebec, Canada Division of Experimental Medicine, McGill University, Montreal, Quebec, Canada Department of Microbiology & Immunology, McGill University, Montreal, Quebec, Canada david.olagnier@mail.mcgill.ca rongtuan.lin@mcgill.ca.
authors: Rongtuan
authors: R
authors: Lin
mesh_terms: D000072283:A549 Cells; D002460:Cell Line; D045744:Cell Line, Tumor; D016207:Cytokines / Q000378:metabolism; D000071457:DEAD Box Protein 58 / Q000378:metabolism*; D006561:Herpes Simplex / Q000378:metabolism*; D018259:Herpesvirus 1, Human / Q000378:metabolism*; D006801:Humans; D007113:Immunity, Innate / Q000502:physiology; D007370:Interferon Type I / Q000378:metabolism; D008565:Membrane Proteins / Q000378:metabolism*; D016328:NF-kappa B / Q000378:metabolism; D011971:Receptors, Immunologic; D050794:STAT1 Transcription Factor / Q000378:metabolism; D050795:STAT2 Transcription Factor / Q000378:metabolism; D015398:Signal Transduction / Q000502:physiology; D015533:Transcriptional Activation / Q000502:physiology; D015854:Up-Regulation / Q000502:physiology*; D000099197:STING Protein
chemical_list: D016207:Cytokines; D000071457:DEAD Box Protein 58; D007370:Interferon Type I; D008565:Membrane Proteins; D016328:NF-kappa B; D011971:Receptors, Immunologic; D050794:STAT1 Transcription Factor; D050795:STAT2 Transcription Factor; C494079:STAT1 protein, human; C532857:STING1 protein, human; D000099197:STING Protein; C452820:RIGI protein, human