Immune Regulation by Regnase‐1 and Related Endoribonucleases

ABSTRACT

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.