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

Abstract

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.

Lymphomagenic CARD11/BCL10/MALT1 signaling drives malignant B-cell proliferation via cooperative NF-κB and JNK activation

“…However, normal antigen receptor signaling recruits the kinase TAK1 to the CBM complex and thus initiates the AP-1 activation cascade (42), and BCL10 can act as a JNK-interacting protein that allows recruitment of JNK2 for c-Jun phosphorylation (43). In addition, the physiological assembly of CBM complexes induces proteolytic activity of the MALT1 paracaspase, which can cleave and inactivate the negative JNK regulator CYLD to enforce the signal for AP-1 activation (44)(45)(46)(47)(48). It is likely similar that those mechanisms would also be engaged by oncogenic CARD11 mutants, but this hypothesis remains to be investigated.…”

Monocyte Chemotactic Protein-induced Protein 1 and 4 Form a Complex but Act Independently in Regulation of Interleukin-6 mRNA Degradation

“…A recent study compared the crystal structure of the putative NYN-RNase domain with other reported RNase proteins and suggested that MCPIP1 is a functional RNase (14). The mRNA targets of MCPIP1 nuclease are now expanding to c-Rel, IL-2, ICOS, Ox40, TNFR2, GATA3, and MCPIP1 self mRNA (13,15,16). MCPIP1 promotes their degradation by targeting their 3Ј-untranslated region (3Ј-UTR) (10,13).…”

“…The mRNA targets of MCPIP1 nuclease are now expanding to c-Rel, IL-2, ICOS, Ox40, TNFR2, GATA3, and MCPIP1 self mRNA (13,15,16). MCPIP1 promotes their degradation by targeting their 3Ј-untranslated region (3Ј-UTR) (10,13). MCPIP1 specifically recognized a stem-loop structure on the 3Ј-UTR of its substrate mRNAs (10).…”

“…MCPIP1 knock-out mice developed spontaneous inflammatory diseases accompanied by splenomegaly, lymphadenopathy, and multiorgan inflammation especially in the lungs (2,11,12). T cellspecific deletion of MCPIP1 produces pathogenic T cells with hyperactivated phenotypes as well as autoimmune diseases (13).…”

Conversion of the LIMA1 tumour suppressor into an oncogenic LMO-like protein by API2–MALT1 in MALT lymphoma

“…6), v-rel avian reticuloendotheliosis viral oncogene homologue B (RelB) 13 , cylindromatosis (CYLD) 14 and regnase-1 (ref. 15). B-cell receptor stimulation by bacterial antigens such as Helicobacter pylori leads to constitutive activation of MALT1 in the CBM signallosomes and cleavage of these substrates.…”