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

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. mehr

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Titel	tRNA-like Transcripts from the NEAT1-MALAT1 Genomic Region Critically Influence Human Innate Immunity and Macrophage Functions
Medien	Cells
Heft	24
Band	11
ISSN	2073-4409
Verfasser	Martina Gast, Vanasa Nageswaran, Andreas Kuss, Ana Tzvetkova, Xiaomin Wang, Liliana Mochmann, Pegah Rad, Stefan Weiss, Prof. Dr. Stefan Simm, Tanja Zeller, Henry Voelzke, Wolfgang Hoffmann, Uwe Völker, Stefan Felix, Marcus Dörr, Antje Beling, Carsten Skurk, David-Manuel Leistner, Bernhard Rauch, Tetsuro Hirose, Bettina Heidecker, Karin Klingel, Shinichi Nakagawa, Wolfram Poller, Filip Swirski, Arash Haghikia, Wolfgang Poller
Seiten	3970
Veröffentlichungsdatum	12.2022
Zitation	Gast, Martina; Nageswaran, Vanasa; Kuss, Andreas; Tzvetkova, Ana; Wang, Xiaomin; Mochmann, Liliana; Rad, Pegah; Weiss, Stefan; Simm, Stefan; Zeller, Tanja; Voelzke, Henry; Hoffmann, Wolfgang; Völker, Uwe; Felix, Stefan; Dörr, Marcus; Beling, Antje; Skurk, Carsten; Leistner, David-Manuel; Rauch, Bernhard; Hirose, Tetsuro; Heidecker, Bettina; Klingel, Karin; Nakagawa, Shinichi; Poller, Wolfram; Swirski, Filip; Haghikia, Arash; Poller, Wolfgang (2022): tRNA-like Transcripts from the NEAT1-MALAT1 Genomic Region Critically Influence Human Innate Immunity and Macrophage Functions. Cells 11 (24), 3970. DOI: 10.3390/cells11243970