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.
Michael et al. (Wed,) studied this question.