Decreased Expression of the Host Long-Noncoding RNA-GM Facilitates Viral Escape by Inhibiting the Kinase activity TBK1 via S-glutathionylation

Immunity. 2020 Dec 15;53(6):1168-1181.e7. doi: 10.1016/j.immuni.2020.11.010.

Abstract

Viruses have evolved multiple strategies to evade elimination by the immune system. Here we examined the contribution of host long noncoding RNAs (lncRNAs) in viral immune evasion. By functional screening of lncRNAs whose expression decreased upon viral infection of macrophages, we identified a lncRNA (lncRNA-GM, Gene Symbol: AK189470.1) that promoted type I interferon (IFN-I) production and inhibited viral replication. Deficiency of lncRNA-GM in mice increased susceptibility to viral infection and impaired IFN-I production. Mechanistically, lncRNA-GM bound to glutathione S-transferase M1 (GSTM1) and blocked GSTM1 interaction with the kinase TBK1, reducing GSTM1-mediated S-glutathionylation of TBK1. Decreased S-glutathionylation enhanced TBK1 activity and downstream production of antiviral mediators. Viral infection reprogrammed intracellular glutathione metabolism and furthermore, an oxidized glutathione mimetic could inhibit TBK1 activity and promote viral replication. Our findings reveal regulation of TBK1 by S-glutathionylation and provide insight into the viral mediated metabolic changes that impact innate immunity and viral evasion.

Keywords: GSSG; GSTM1; TBK1; glutathione metabolism; innate immunity; interferons; long noncoding RNA; virus infection.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Glutathione / metabolism*
  • Glutathione Transferase / metabolism
  • Humans
  • Immune Evasion*
  • Immunity, Innate
  • Interferon Regulatory Factor-3 / metabolism
  • Interferon Type I / metabolism
  • Macrophages / immunology
  • Macrophages / metabolism
  • Mice
  • Protein Processing, Post-Translational*
  • Protein Serine-Threonine Kinases / metabolism*
  • RNA, Long Noncoding / genetics
  • RNA, Long Noncoding / metabolism*
  • Signal Transduction
  • Virus Diseases / genetics
  • Virus Diseases / immunology
  • Virus Diseases / metabolism
  • Virus Replication

Substances

  • Interferon Regulatory Factor-3
  • Interferon Type I
  • Irf3 protein, mouse
  • RNA, Long Noncoding
  • Glutathione Transferase
  • glutathione S-transferase M1
  • Tbk1 protein, mouse
  • Protein Serine-Threonine Kinases
  • Glutathione