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

SUMMARY 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 Regnase-1 controls NFKBIZ expression through a precise and modular RNA degradation mechanism. The structured core element undergoes specific endonucleolytic cleavage, while flanking upstream and downstream stem–loop modules, previously implicated in Regnase-1 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 Regnase-1–mediated control of NFKBIZ, linking its cleavage activity to both lymphomagenesis and viral pathogenesis.