Immune Regulation by Regnase-1 and Related Endoribonucleases

Regnase-1 (ZC3H12A) is a stem-loop (SL)-recognizing endoribonuclease that couples immune stimulation to selective mRNA decay. Although originally characterized as a negative regulator of inflammatory cytokine expression, recent studies have expanded this view by placing Regnase-1 within a broader network of SL-recognizing RNA decay factors, including Roquin proteins and Regnase-3, and by revealing context-dependent functions in immune and nonimmune cells. Through regulation of transcripts encoding cytokines, costimulatory molecules, and transcriptional regulators, Regnase-1 restrains innate and adaptive immune activation, but biological output varies according to cell type, tissue environment, disease stage, and mode of perturbation. In T cells, including engineered T cells used in adoptive cell therapy, Regnase-1 inhibition can enhance antitumor activity in preclinical models, whereas in epithelial tissues Regnase-1 can limit inflammatory circuits that affect host defense, tissue injury, and inflammation-associated tumorigenesis. Structure-targeting antisense oligonucleotides and genome-editing approaches have further raised the possibility of therapeutically modulating Regnase-dependent RNA decay. In this Review, we discuss molecular mechanisms of Regnase-1-mediated mRNA decay, context-dependent functions across tissues and diseases, and the opportunities and limitations of targeting this pathway therapeutically.