Regulation of NFKBIZ by precise Regnase-1 endoribonuclease cleavage and subsequent uridylation

A conserved sequence in the 3′UTR of NFKBIZ mRNA has long been recognized as a regulator of cytokine production and interferon responses. We show that the endoribonuclease Regnase1 controls NFKBIZ expression through a precise and modular RNA degradation mechanism. The structured core element undergoes specific endonucleolytic cleavage, while flanking upstream and downstream stemloop modules, previously implicated in Regnase1 recognition, act cooperatively to enhance cleavage efficiency by ~25-fold. Following cleavage, the upstream fragment is rapidly uridylated, accelerating decay of the NFKBIZ open reading frame. This pathway explains how driver mutations found in this RNA region responsible for diffuse large B-cell lymphoma elevate NFKBIZ expression and how a segment of the SARS CoV 2 genome previously linked to NFKBIZ activation suppresses Regnase-1 cleavage via hybridization to this regulatory RNA segment. Together, these findings define a mechanistic framework for Regnase1 mediated control of NFKBIZ, linking its cleavage activity to both lymphomagenesis and viral pathogenesis.