The regnase family in autoimmune diseases: a regnase-1-centered perspective on cellular heterogeneity

The Regnase family comprises RNA-binding endoribonucleases that control immune responses by regulating the stability of inflammation-associated messenger RNA (mRNA). Evidence is most extensive for Regnase-1, whereas the other family members differ in cellular distribution, RNA substrates, and contributions across disease stages. Regnase activity is shaped by the timing of ribonuclease inactivation and recovery, the target-RNA repertoire of each cell type, and intercellular communication. Transient loss of activity after stimulation permits immune effector programs to begin, but failure to restore activity can prolong inflammation. Conversely, persistently high activity in selected T-cell populations or during tissue repair may also disturb homeostasis. Regnase-associated pathology is therefore better understood as a mismatch between RNA decay and the requirements of a particular cell and disease stage than as a uniform increase or decrease in expression. Oligonucleotides targeting autoregulatory stem-loops in the Regnase-1 3' untranslated region, together with local protein or gene augmentation, have provided preclinical proof of concept. Other delivery and protein-regulation platforms remain exploratory. Progress toward therapy will require temporally resolved human samples and direct measurements of protein state, RNA binding, and target decay to define interventions that are cell selective, reversible, and confined to an appropriate disease window.