A microRNA generated via lysosomal processing of ribosomal RNA suppresses proinflammatory responses

Transient induction of a miRNA derived via lysosomal processing of 28S rRNA enables cells to distinguish between temporary mild stress and chronic stress that calls for a proinflammatory response. ER stress underlies numerous severe pathologies. We have metabolically perturbed normal fibroblasts to study the biological roles of microRNAs (miRs) under mild and extended ER stress. We now report that miR-4488 quenches inflammation-associated gene expression in such metabolically perturbed cells. Remarkably, generation of miR-4488 is Drosha-independent. Furthermore, we define miR-4488 as a noncanonical miRNA derived from the expansion segment ES7L of the 28S ribosomal RNA. Moreover, its generation involves the autophagy–lysosome route and is inhibited when this pathway is blocked, thus unveiling an anti-inflammatory role for ribosomal RNA and lysosomes, engaged at the onset of stress. Mechanistically, miR-4488 suppresses the expression of NFKB2 and RELB, whose mRNAs specifically associate with miR-4488 exclusively upon stress. This selectivity suggests that miR-4488 may bear promise for treating mild ER stress–associated diseases. Graphical Abstract lsa;9/7/e202503536/GA F1 GA