tRNA-like Transcripts from the NEAT1-MALAT1 Genomic Region Critically Influence Human Innate Immunity and Macrophage Functions

Martina Gast, Vanasa Nageswaran, Andreas W. Kuss, Ana Tzvetkova, Xiaomin Wang, Liliana H. Mochmann, Pegah Ramezani Rad, Stefan Weiss, Stefan Simm, Tanja Zeller, Henry Voelzke, Wolfgang Hoffmann, Uwe Völker, Stefan B. Felix, Marcus Dörr, Antje Beling, Carsten Skurk, David Manuel Leistner, Bernhard H. Rauch, Tetsuro HiroseBettina Heidecker, Karin Klingel, Shinichi Nakagawa, Wolfram C. Poller, Filip K. Swirski, Arash Haghikia, Wolfgang Poller

Research output: Contribution to journalArticlepeer-review

5 Scopus citations

Abstract

The evolutionary conserved NEAT1-MALAT1 gene cluster generates large noncoding transcripts remaining nuclear, while tRNA-like transcripts (mascRNA, menRNA) enzymatically generated from these precursors translocate to the cytosol. Whereas functions have been assigned to the nuclear transcripts, data on biological functions of the small cytosolic transcripts are sparse. We previously found NEAT1−/− and MALAT1−/− mice to display massive atherosclerosis and vascular inflammation. Here, employing selective targeted disruption of menRNA or mascRNA, we investigate the tRNA-like molecules as critical components of innate immunity. CRISPR-generated human ΔmascRNA and ΔmenRNA monocytes/macrophages display defective innate immune sensing, loss of cytokine control, imbalance of growth/angiogenic factor expression impacting upon angiogenesis, and altered cell–cell interaction systems. Antiviral response, foam cell formation/oxLDL uptake, and M1/M2 polarization are defective in ΔmascRNA/ΔmenRNA macrophages, defining first biological functions of menRNA and describing new functions of mascRNA. menRNA and mascRNA represent novel components of innate immunity arising from the noncoding genome. They appear as prototypes of a new class of noncoding RNAs distinct from others (miRNAs, siRNAs) by biosynthetic pathway and intracellular kinetics. Their NEAT1-MALAT1 region of origin appears as archetype of a functionally highly integrated RNA processing system.

Original languageEnglish
Article number3970
JournalCells
Volume11
Issue number24
DOIs
StatePublished - Dec 2022

Keywords

  • evolutionary genetics
  • immunogenetics
  • immunology
  • innate immunity
  • noncoding genome
  • tRNA biology

Fingerprint

Dive into the research topics of 'tRNA-like Transcripts from the NEAT1-MALAT1 Genomic Region Critically Influence Human Innate Immunity and Macrophage Functions'. Together they form a unique fingerprint.

Cite this