HEXIM1 and NEAT1 Long Non-coding RNA Form a Multi-subunit Complex that Regulates DNA-Mediated Innate Immune Response

Mol Cell. 2017 Aug 3;67(3):387-399.e5. doi: 10.1016/j.molcel.2017.06.020. Epub 2017 Jul 14.

Abstract

The DNA-mediated innate immune response underpins anti-microbial defenses and certain autoimmune diseases. Here we used immunoprecipitation, mass spectrometry, and RNA sequencing to identify a ribonuclear complex built around HEXIM1 and the long non-coding RNA NEAT1 that we dubbed the HEXIM1-DNA-PK-paraspeckle components-ribonucleoprotein complex (HDP-RNP). The HDP-RNP contains DNA-PK subunits (DNAPKc, Ku70, and Ku80) and paraspeckle proteins (SFPQ, NONO, PSPC1, RBM14, and MATRIN3). We show that binding of HEXIM1 to NEAT1 is required for its assembly. We further demonstrate that the HDP-RNP is required for the innate immune response to foreign DNA, through the cGAS-STING-IRF3 pathway. The HDP-RNP interacts with cGAS and its partner PQBP1, and their interaction is remodeled by foreign DNA. Remodeling leads to the release of paraspeckle proteins, recruitment of STING, and activation of DNAPKc and IRF3. Our study establishes the HDP-RNP as a key nuclear regulator of DNA-mediated activation of innate immune response through the cGAS-STING pathway.

Keywords: DNA-PK; HEXIM1; NEAT1; cGAS; herpesvirus; innate immune response; interferon stimulatory DNA; paraspeckles.

MeSH terms

  • Calcium-Binding Proteins / genetics
  • Calcium-Binding Proteins / immunology
  • Calcium-Binding Proteins / metabolism
  • DNA / genetics
  • DNA / immunology*
  • DNA / metabolism
  • DNA-Binding Proteins
  • HEK293 Cells
  • HeLa Cells
  • Herpesvirus 8, Human / immunology*
  • Host-Pathogen Interactions
  • Human Umbilical Vein Endothelial Cells / immunology
  • Human Umbilical Vein Endothelial Cells / metabolism
  • Human Umbilical Vein Endothelial Cells / virology
  • Humans
  • Immunity, Innate*
  • Interferon Regulatory Factor-3 / genetics
  • Interferon Regulatory Factor-3 / immunology
  • Interferon Regulatory Factor-3 / metabolism
  • Intracellular Signaling Peptides and Proteins / genetics
  • Intracellular Signaling Peptides and Proteins / immunology
  • Intracellular Signaling Peptides and Proteins / metabolism
  • Ku Autoantigen / genetics
  • Ku Autoantigen / immunology
  • Ku Autoantigen / metabolism
  • Membrane Proteins / genetics
  • Membrane Proteins / immunology
  • Membrane Proteins / metabolism
  • Multiprotein Complexes
  • Nuclear Matrix-Associated Proteins / genetics
  • Nuclear Matrix-Associated Proteins / immunology
  • Nuclear Matrix-Associated Proteins / metabolism
  • Nuclear Proteins / genetics
  • Nuclear Proteins / immunology
  • Nuclear Proteins / metabolism
  • Nucleotidyltransferases / genetics
  • Nucleotidyltransferases / immunology
  • Nucleotidyltransferases / metabolism
  • Octamer Transcription Factors / genetics
  • Octamer Transcription Factors / immunology
  • Octamer Transcription Factors / metabolism
  • PTB-Associated Splicing Factor / genetics
  • PTB-Associated Splicing Factor / immunology
  • PTB-Associated Splicing Factor / metabolism
  • Protein Binding
  • RNA Interference
  • RNA, Long Noncoding / genetics
  • RNA, Long Noncoding / immunology*
  • RNA, Long Noncoding / metabolism
  • RNA-Binding Proteins / genetics
  • RNA-Binding Proteins / immunology*
  • RNA-Binding Proteins / metabolism
  • Signal Transduction
  • Transcription Factors
  • Transfection

Substances

  • CIB1 protein, human
  • Calcium-Binding Proteins
  • DNA-Binding Proteins
  • HEXIM1 protein, human
  • IRF3 protein, human
  • Interferon Regulatory Factor-3
  • Intracellular Signaling Peptides and Proteins
  • MATR3 protein, human
  • Membrane Proteins
  • Multiprotein Complexes
  • NEAT1 long non-coding RNA, human
  • NONO protein, human
  • Nuclear Matrix-Associated Proteins
  • Nuclear Proteins
  • Octamer Transcription Factors
  • PSPC1 protein, human
  • PTB-Associated Splicing Factor
  • RBM14 protein, human
  • RNA, Long Noncoding
  • RNA-Binding Proteins
  • STING1 protein, human
  • Transcription Factors
  • DNA
  • Nucleotidyltransferases
  • cGAS protein, human
  • XRCC5 protein, human
  • Xrcc6 protein, human
  • Ku Autoantigen