Malt1-Induced Cleavage of Regnase-1 in CD4+ Helper T Cells Regulates Immune Activation

Regnase-1 (also known as Zc3h12a and MCPIP1) is an RNase that destabilizes a set of mRNAs, including Il6 and Il12b, through cleavage of their 3′ UTRs. Although Regnase-1 inactivation leads to development of an autoimmune disease characterized by T cell activation and hyperimmunoglobulinemia in mice, the mechanism of Regnase-1-mediated immune regulation has remained unclear. We show that Regnase-1 is essential for preventing aberrant effector CD4+ T cell generation cell autonomously. Moreover, in T cells, Regnase-1 regulates the mRNAs of a set of genes, including c-Rel, Ox40, and Il2, through cleavage of their 3′ UTRs. Interestingly, T cell receptor (TCR) stimulation leads to cleavage of Regnase-1 at R111 by Malt1/paracaspase, freeing T cells from Regnase-1-mediated suppression. Furthermore, Malt1 protease activity is critical for controlling the mRNA stability of T cell effector genes. Collectively, these results indicate that dynamic control of Regnase-1 expression in T cells is critical for controlling T cell activation. [Display omitted] •T cell activation is balanced by transcriptional and posttranscriptional regulation•Regnase-1 downregulates genes related to T cell effector function by degrading mRNAs•Regnase-1 in CD4+ T cells is responsible for suppressing autoimmune disease in mice•TCR signaling leads to Regnase-1 cleavage by Malt1, facilitating T cell activation The RNase Regnase-1 limits autoimmunity by degrading mRNAs required for T cell activation. Immune activation requires its cleavage by the protease Malt1.