Stimulator of interferon genes (STING) is an essential proviral host factor for human rhinovirus species A and C

Proc Natl Acad Sci U S A. 2020 Nov 3;117(44):27598-27607. doi: 10.1073/pnas.2014940117. Epub 2020 Oct 15.


Human rhinoviruses (RVs) are positive-strand RNA viruses that cause respiratory tract disease in children and adults. Here we show that the innate immune signaling protein STING is required for efficient replication of members of two distinct RV species, RV-A and RV-C. The host factor activity of STING was identified in a genome-wide RNA interference (RNAi) screen and confirmed in primary human small airway epithelial cells. Replication of RV-A serotypes was strictly dependent on STING, whereas RV-B serotypes were notably less dependent. Subgenomic RV-A and RV-C RNA replicons failed to amplify in the absence of STING, revealing it to be required for a step in RNA replication. STING was expressed on phosphatidylinositol 4-phosphate (PI4P)-enriched membranes and was enriched in RV-A16 compared with RV-B14 replication organelles isolated in isopycnic gradients. The host factor activity of STING was species-specific, as murine STING (mSTING) did not rescue RV-A16 replication in STING-deficient cells. This species specificity mapped primarily to the cytoplasmic, ligand-binding domain of STING. Mouse-adaptive mutations in the RV-A16 2C protein allowed for robust replication in cells expressing mSTING, suggesting a role for 2C in recruiting STING to RV-A replication organelles. Palmitoylation of STING was not required for RV-A16 replication, nor was the C-terminal tail of STING that mediates IRF3 signaling. Despite co-opting STING to promote its replication, interferon signaling in response to STING agonists remained intact in RV-A16 infected cells. These data demonstrate a surprising requirement for a key host mediator of innate immunity to DNA viruses in the life cycle of a small pathogenic RNA virus.

Keywords: cGAS; host range; innate immunity; phosphatidylinositol 4-phosphate; replication organelle.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Carrier Proteins / genetics
  • Carrier Proteins / metabolism
  • Common Cold / immunology
  • Common Cold / virology
  • Enterovirus / genetics
  • Enterovirus / immunology
  • Enterovirus / metabolism
  • Enterovirus / pathogenicity*
  • HeLa Cells
  • Host-Pathogen Interactions / immunology*
  • Humans
  • Immunity, Innate
  • Interferon Regulatory Factor-3 / metabolism
  • Lipoylation
  • Membrane Proteins / agonists
  • Membrane Proteins / metabolism*
  • Mutation
  • Protein Domains / genetics
  • Signal Transduction
  • Species Specificity
  • Viral Nonstructural Proteins / genetics
  • Viral Nonstructural Proteins / metabolism
  • Virus Replication / immunology*


  • Carrier Proteins
  • IRF3 protein, human
  • Interferon Regulatory Factor-3
  • Membrane Proteins
  • STING1 protein, human
  • Sting1 protein, mouse
  • Viral Nonstructural Proteins
  • 2C protein, viral

Supplementary concepts

  • Rhinovirus A
  • Rhinovirus C