UV Light Potentiates STING (Stimulator of Interferon Genes)-dependent Innate Immune Signaling through Deregulation of ULK1 (Unc51-like Kinase 1)

J Biol Chem. 2015 May 8;290(19):12184-94. doi: 10.1074/jbc.M115.649301. Epub 2015 Mar 19.

Abstract

The mechanism by which ultraviolet (UV) wavelengths of sunlight trigger or exacerbate the symptoms of the autoimmune disorder lupus erythematosus is not known but may involve a role for the innate immune system. Here we show that UV radiation potentiates STING (stimulator of interferon genes)-dependent activation of the immune signaling transcription factor interferon regulatory factor 3 (IRF3) in response to cytosolic DNA and cyclic dinucleotides in keratinocytes and other human cells. Furthermore, we find that modulation of this innate immune response also occurs with UV-mimetic chemical carcinogens and in a manner that is independent of DNA repair and several DNA damage and cell stress response signaling pathways. Rather, we find that the stimulation of STING-dependent IRF3 activation by UV is due to apoptotic signaling-dependent disruption of ULK1 (Unc51-like kinase 1), a pro-autophagic protein that negatively regulates STING. Thus, deregulation of ULK1 signaling by UV-induced DNA damage may contribute to the negative effects of sunlight UV exposure in patients with autoimmune disorders.

Keywords: Apoptosis; Autoimmunity; Autophagy; Cell Signaling; DNA Damage; DNA Damage Response; DNA Repair; Innate Immunity; Interferon; Nucleotide Excision Repair.

Publication types

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

MeSH terms

  • Apoptosis
  • Autoimmunity
  • Autophagy
  • Autophagy-Related Protein-1 Homolog
  • Cell Line
  • DNA Damage
  • DNA Repair
  • Gene Expression Regulation
  • HEK293 Cells
  • Humans
  • Immunity, Innate*
  • Interferon Regulatory Factor-3 / metabolism
  • Interferons / metabolism*
  • Intracellular Signaling Peptides and Proteins / metabolism*
  • Keratinocytes / metabolism
  • Membrane Proteins / metabolism*
  • Phosphorylation
  • Protein-Serine-Threonine Kinases / metabolism*
  • RNA Interference
  • Signal Transduction
  • Ultraviolet Rays*

Substances

  • IRF3 protein, human
  • Interferon Regulatory Factor-3
  • Intracellular Signaling Peptides and Proteins
  • Membrane Proteins
  • STING1 protein, human
  • Interferons
  • Autophagy-Related Protein-1 Homolog
  • Protein-Serine-Threonine Kinases
  • ULK1 protein, human