Kisspeptin/GPR54 signaling restricts antiviral innate immune response through regulating calcineurin phosphatase activity

Sci Adv. 2018 Aug 8;4(8):eaas9784. doi: 10.1126/sciadv.aas9784. eCollection 2018 Aug.


G protein-coupled receptor 54 (GPR54), the key receptor for the neuropeptide hormone kisspeptin, plays essential roles in regulating puberty development and cancer metastasis. However, its role in the antiviral innate immune response is unknown. We report that virus-induced type I interferon (IFN-I) production was significantly enhanced in Gpr54-deficient cells and mice and resulted in restricted viral replication. We found a marked increase of kisspeptin in mouse serum during viral infection, which, in turn, impaired IFN-I production and antiviral immunity through the GPR54/calcineurin axis. Mechanistically, kisspeptin/GPR54 signaling recruited calcineurin and increased its phosphatase activity to dephosphorylate and deactivate TANK [tumor necrosis factor receptor-associated factor (TRAF) family member-associated NF-κB activator]-binding kinase 1 (TBK1) in a Ca2+-dependent manner. Thus, our data reveal a kisspeptin/GPR54/calcineurin-mediated immune evasion pathway exploited by virus through the negative feedback loop of TBK1 signaling. These findings also provide insights into the function and cross-talk of kisspeptin, a known neuropeptide hormone, in antiviral innate immune response.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Calcineurin
  • Gene Expression Regulation
  • Herpes Simplex / immunology*
  • Herpes Simplex / virology
  • Herpesvirus 1, Human / immunology
  • Immunity, Innate / immunology*
  • Interferon Type I / metabolism*
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Protein-Serine-Threonine Kinases / metabolism*
  • Receptors, Kisspeptin-1 / physiology*
  • Rhabdoviridae Infections / immunology*
  • Rhabdoviridae Infections / virology
  • Signal Transduction
  • Vesicular stomatitis Indiana virus
  • Virus Replication / immunology*


  • Interferon Type I
  • Kiss1r protein, mouse
  • Receptors, Kisspeptin-1
  • Protein-Serine-Threonine Kinases
  • TBK1 protein, human
  • Calcineurin