Message in a bottle: lessons learned from antagonism of STING signalling during RNA virus infection

Abstract

STING has emerged in recent years as an important signalling adaptor in the activation of type I interferon responses during infection with DNA viruses and bacteria. An increasing body of evidence suggests that STING also modulates responses to RNA viruses, though the mechanisms remain less clear. In this review, we give a brief overview of the ways in which STING facilitates sensing of RNA viruses. These include modulation of RIG-I-dependent responses through STING's interaction with MAVS, and more speculative mechanisms involving the DNA sensor cGAS and sensing of membrane remodelling events. We then provide an in-depth literature review to summarise the known mechanisms by which RNA viruses of the families Flaviviridae and Coronaviridae evade sensing through STING. Our own work has shown that the NS2B/3 protease complex of the flavivirus dengue virus binds and cleaves STING, and that an inability to degrade murine STING may contribute to host restriction in this virus. We contrast this to the mechanism employed by the distantly related hepacivirus hepatitis C virus, in which STING is bound and inactivated by the NS4B protein. Finally, we discuss STING antagonism in the coronaviruses SARS coronavirus and human coronavirus NL63, which disrupt K63-linked polyubiquitination and dimerisation of STING (both of which are required for STING-mediated activation of IRF-3) via their papain-like proteases. We draw parallels with less-well characterised mechanisms of STING antagonism in related viruses, and place our current knowledge in the context of species tropism restrictions that potentially affect the emergence of new human pathogens.

Keywords: Dengue; Hepatitis C virus; Immune evasion; SARS coronavirus; STING.

Copyright © 2014 The Authors. Published by Elsevier Ltd.. All rights reserved.

Figures

Fig. 1

STING signalling during RNA virus infection. Inactive STING resides in membranes of the ER, MAM and mitochondria (M*). Following its activation, STING dimerises and relocalises to perinuclear punctate domains, where it interacts with TBK1 to phosphorylate IRF-3. Activated STING is also modified by phosphorylation and K63-linked polyubiquitination. Following its activation, IRF-3 dimerises and translocates to the nucleus, where it induces the transcription of the type I interferons IFN-α and IFN-β. RNA viruses have been proposed to be sensed by three distinct mechanisms in relation to STING activation. (1) Viral dsRNA replication intermediates and stem-loop structures, and the 5′-triphosphates of uncapped viral RNAs are recognised by RIG-I, which associates with MAVS and STING at MAMs to activate STING. (2) The DNA sensor cGAS has been linked to the sensing of positive-sense RNA viruses by an as-yet undefined mechanism. In this scenario, cGAS produces the messenger molecule cGAMP after detecting RNA virus infection, and cGAMP binds and activates STING. (3) Viral fusion events at the plasma membrane have been shown to activate STING by a poorly-defined mechanism involving PI(3)K and phospholipase C-γ (PLC-γ). For simplicity, only signalling molecules referred to in the main text are shown.

Fig. 2

Flaviviridae phylogenetic tree and genome organisation. (A) Flaviviridae family tree. Viruses of relevance to this review, and other representative viruses, shown. (B) Mosquito-borne flavivirus (∼11 kb) and (C) hepacivirus (∼9.6 kb) genome organisation (not to scale). Structural proteins are in black. STING antagonists are highlighted in grey. A STING antagonist function has been described for the YFV NS4B protein, but not for the DENV NS4B. Additional known functions for proteins discussed in this review are also given. Triangles indicate cleavage sites for the flavivirus NS2B/3 (B) or hepacivirus NS3/4A (C) proteases. The HCV polyuridine tract ((U/UC)n) is a well-known PAMP that induces type I IFN production. Note that the hepacivirus genome is uncapped. Members of the Flaviviridae lack a poly(A) tail. Viruses not defined elsewhere; CSFV, classical swine fever virus; BDV, bovine diarrhoea virus; GBV, GV virus.

Fig. 3

Coronavirinae phylogenetic tree, genome organisation, and nsp3 functional domains. (A) Coronavirinae family tree. Viruses of relevance to this review, and other representative viruses, shown. (B) SARS-CoV genome organisation (not to scale). Structural proteins are in black. The two polyproteins (1a and 1ab) translated by ribosomal frameshifting are shown. Triangles indicate PLpro cleavage sites; the remaining polyprotein cleavage sites are processed by the main 3C-like protease. The 3′ structural and additional accessory proteins differ among coronaviruses. Functional domains encoded by the SARS-CoV (C) and the HCoV-NL63 (D) nsp3 are also shown (not to scale). Domains linked to STING antagonism are highlighted in grey; the precise function of the transmembrane (TM) domain remains unknown. Terms not defined elsewhere; TCoV, turkey coronavirus; IBV, infectious bronchitis virus; Ubl, ubiquitin-like domain; Ac, acidic domain; ADRP, poly(ADP-ribose)-binding/ADP-ribose-1′-phosphatase macrodomain; NAB, nucleic acid-binding domain; G2M, betacoronavirus marker; Y domain, highly conserved coronavirus domain.