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

• Published in: Cells (Basel, Switzerland) Vol. 11; no. 24; p. 3970
• Main Authors: Gast, Martina, Nageswaran, Vanasa, Kuss, Andreas W, Tzvetkova, Ana, Wang, Xiaomin, Mochmann, Liliana H, Rad, Pegah Ramezani, Weiss, Stefan, Simm, Stefan, Zeller, Tanja, Voelzke, Henry, Hoffmann, Wolfgang, Völker, Uwe, Felix, Stefan B, Dörr, Marcus, Beling, Antje, Skurk, Carsten, Leistner, David-Manuel, Rauch, Bernhard H, Hirose, Tetsuro, Heidecker, Bettina, Klingel, Karin, Nakagawa, Shinichi, Poller, Wolfram C, Swirski, Filip K, Haghikia, Arash, Poller, Wolfgang
• Format: Journal Article
• Language: English
• Published: Switzerland MDPI AG 08-12-2022; MDPI
• Subjects: Angiogenesis; Arteriosclerosis; Cloning; CRISPR; Cytosol; Editing; Ethics; Evolutionary conservation; evolutionary genetics; Gene expression; Genomics; Humans; Immunity, Innate - genetics; Immunity, Innate - immunology; immunogenetics; immunology; Innate immunity; Macrophages; Macrophages - immunology; Monocytes; noncoding genome; RNA processing; RNA, Long Noncoding - genetics; RNA, Long Noncoding - immunology; RNA, Transfer - genetics; RNA, Transfer - immunology; siRNA; Transfer RNA; Trends; tRNA; tRNA biology; immunogenetics; noncoding genome; tRNA biology; innate immunity; immunology; evolutionary genetics
• ISSN: 2073-4409; 2073-4409
• DOI: 10.3390/cells11243970

The evolutionary conserved
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
and
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
region of origin appears as archetype of a functionally highly integrated RNA processing system.