Novel 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. NEAT1-/- and MALAT1-/- mice display massive atherosclerosis and vascular inflammation. Here, we identify the tRNA-like molecules as critical components of innate immunity. They appear as prototypes of a new class of noncoding RNAs distinct from others (miRNAs, siRNAs) by biosynthetic pathway and intracellular kinetics. 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 the tRNA-like molecules’ first described biological functions. menRNA and mascRNA represent novel components of innate immunity arising from the noncoding genome. Their NEAT1-MALAT1 region of origin appears as archetype of a functionally highly integrated RNA processing system.