TRAF3 activates STING-mediated suppression of EV-A71 and target of viral evasion

Signal Transduct Target Ther. 2023 Feb 24;8(1):79. doi: 10.1038/s41392-022-01287-2.


Innate immunity represents one of the main host responses to viral infection.1-3 STING (Stimulator of interferon genes), a crucial immune adapter functioning in host cells, mediates cGAS (Cyclic GMP-AMP Synthase) sensing of exogenous and endogenous DNA fragments and generates innate immune responses.4 Whether STING activation was involved in infection and replication of enterovirus remains largely unknown. In the present study, we discovered that human enterovirus A71 (EV-A71) infection triggered STING activation in a cGAS dependent manner. EV-A71 infection caused mitochondrial damage and the discharge of mitochondrial DNA into the cytosol of infected cells. However, during EV-A71 infection, cGAS-STING activation was attenuated. EV-A71 proteins were screened and the viral protease 2Apro had the greatest capacity to inhibit cGAS-STING activation. We identified TRAF3 as an important factor during STING activation and as a target of 2Apro. Supplement of TRAF3 rescued cGAS-STING activation suppression by 2Apro. TRAF3 supported STING activation mediated TBK1 phosphorylation. Moreover, we found that 2Apro protease activity was essential for inhibiting STING activation. Furthermore, EV-D68 and CV-A16 infection also triggered STING activation. The viral protease 2Apro from EV-D68 and CV-A16 also had the ability to inhibit STING activation. As STING activation prior to EV-A71 infection generated cellular resistance to EV-A71 replication, blocking EV-A71-mediated STING suppression represents a new anti-viral target.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Antigens, Viral
  • Enterovirus A, Human* / physiology
  • Humans
  • Immunity, Innate
  • Membrane Proteins*
  • Nucleotidyltransferases / genetics
  • TNF Receptor-Associated Factor 3* / genetics
  • Viral Proteases


  • Antigens, Viral
  • Nucleotidyltransferases
  • TNF Receptor-Associated Factor 3
  • TRAF3 protein, human
  • Viral Proteases
  • STING1 protein, human
  • Membrane Proteins