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

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.
Mehdi Morchikh 1,  Alexandra Cribier 2,  Raoul Raffel 3,  Sonia Amraoui 4,  Julien Cau 5,  Dany Severac 6,  Emeric Dubois 6,  Olivier Schwartz 4,  Yamina Bennasser 3,  Monsef Benkirane 7
Affiliations

Affiliations

  • 1 Institut de Génétique Humaine, Laboratoire de Virologie Moléculaire, Université de Montpellier, CNRS UMR9002, 34000 Montpellier, France. Electronic address: mehdi.morchikh@igh.cnrs.fr.
  • 2 Institut de Génétique Humaine, Laboratoire de Virologie Moléculaire, Université de Montpellier, CNRS UMR9002, 34000 Montpellier, France. Electronic address: alexandra.cribier@igh.cnrs.fr.
  • 3 Institut de Génétique Humaine, Laboratoire de Virologie Moléculaire, Université de Montpellier, CNRS UMR9002, 34000 Montpellier, France.
  • 4 Institut Pasteur, Virus and Immunity Unit, URA CNRS 3015, 75015 Paris, France.
  • 5 MRI-Montpellier, Biocampus, Montpellier, 34095 France; IGH CNRS- Université de Montpellier, UMR9002, 34396 Montpellier, France.
  • 6 MGX-Montpellier GenomiX, 34094 Montpellier, France.
  • 7 Institut de Génétique Humaine, Laboratoire de Virologie Moléculaire, Université de Montpellier, CNRS UMR9002, 34000 Montpellier, France. Electronic address: monsef.benkirane@igh.cnrs.fr.
PMID: 28712728 DOI: 10.1016/j.molcel.2017.06.020
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.

Figures