Uncoupling Malt1 Threshold Function from Paracaspase Activity Results in Destructive Autoimmune Inflammation

Abstract

The paracaspase Malt1 is a central regulator of antigen receptor signaling that is frequently mutated in human lymphoma. As a scaffold, it assembles protein complexes for NF-κB activation, and its proteolytic domain cleaves negative NF-κB regulators for signal enforcement. Still, the physiological functions of Malt1-protease are unknown. We demonstrate that targeted Malt1-paracaspase inactivation induces a lethal inflammatory syndrome with lymphocyte-dependent neurodegeneration in vivo. Paracaspase activity is essential for regulatory T cell (Treg) and innate-like B cell development, but it is largely dispensable for overcoming Malt1-dependent thresholds for lymphocyte activation. In addition to NF-κB inhibitors, Malt1 cleaves an entire set of mRNA stability regulators, including Roquin-1, Roquin-2, and Regnase-1, and paracaspase inactivation results in excessive interferon gamma (IFNγ) production by effector lymphocytes that drive pathology. Together, our results reveal distinct threshold and modulatory functions of Malt1 that differentially control lymphocyte differentiation and activation pathways and demonstrate that selective paracaspase blockage skews systemic immunity toward destructive autoinflammation.

The paracaspase MALT1 cleaves the LUBAC subunit HOIL1 during antigen receptor signaling

“…Nevertheless, our data suggests that HOIL1 belongs, together with A20 and RelB (Coornaert et al, 2008;Hailfinger et al, 2011), to a group of proteins that curtail NF-κB when not cleaved by MALT1. In that sense, defining whether HOIL1 is harmful when left intact in lymphocytes and contributes to the striking phenotype of MALT1 protease-dead mice would be of interest (Bornancin et al, 2015;Gewies et al, 2014;Jaworski et al, 2014). We also provide evidence that exacerbated MALT1 activity in ABC DLBCL cells results in the constitutive cleavage of HOIL1.…”

“…MALT1 exerts dual complementary roles in TCR signaling (Hailfinger et al, 2014). Its scaffold function marshals NF-κB activation, whereas proteolytic activity governs optimal proliferation and cytokine production (Bornancin et al, 2015;Gewies et al, 2014;Jaworski et al, 2014). MALT1 enzyme also regulates NF-κB signaling independently of the IKK complex by cleaving substrates including A20, RelB and MALT1 itself (Baens et al, 2014;Coornaert et al, 2008;Hailfinger et al, 2011).…”

“…MALT1 paracaspase activity exerts a central function in optimally orchestrating an immune response (Bornancin et al, 2015;Gewies et al, 2014;Jaworski et al, 2014). Yet, the full spectrum of its substrates continues to be elucidated (Demeyer et al, 2016).…”

“…In addition to its scaffold function during NF-κB activation, MALT1 catalytic activity shapes the immune response (Bornancin et al, 2015;Gewies et al, 2014;Jaworski et al, 2014). MALT1 protease dictates T-cell receptor (TCR)-mediated proliferation, optimal IL-2 production, and Th17 differentiation, and MALT1 enzyme inactivation in mice establishes a lethal multi-organ inflammatory syndrome (Bornancin et al, 2015;Gewies et al, 2014;Jaworski et al, 2014). Known substrates include regulators of NF-κB [A20 (also known as TNFAIP3), RelB and MALT1], adhesion (BCL10), JNK and AP-1 (CYLD), and mTORC1, as well as mRNA stability factors (Regnase-1 and Roquin-1/2) (Demeyer et al, 2016).…”

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.…”