Uncoupling Malt1 threshold function from paracaspase activity results in destructive autoimmune inflammation. Mus musculus

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-kB activation, and its proteolytic domain cleaves negative NF-kB 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 and innate-like B-cell development, but it is largely dispensable for overcoming Malt1-dependent thresholds for lymphocyte activation. In addition to NF-kB inhibitors, Malt1 cleaves an entire set of mRNA stability regulators, including Roquin-1, Roquin-2 and Regnase-1, and paracaspase inactivation results in excessive IFNγ production by effector lymphocytes that drives 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 towards destructive autoinflammation. Overall design: Total RNA obtained from T cells with (1h and 4 h) and without stimulation, 3 biological replicates, 3 genotypes (Malt+/-, Malt-/-, MaltPM/-)

副半胱天冬酶（paracaspase）Malt1是抗原受体信号通路的核心调控因子，在人类淋巴瘤中常发生突变。作为支架蛋白，它组装参与核因子κB（NF-κB）激活的蛋白质复合物，其蛋白水解结构域可切割NF-κB的负调控因子以强化信号传导。然而，Malt1蛋白酶的生理功能迄今仍不明确。本研究证实，靶向灭活Malt1副半胱天冬酶可在活体中诱导致命性炎症综合征，并伴随淋巴细胞依赖性神经退行性病变。副半胱天冬酶活性对于调节性T细胞及先天样B细胞的发育至关重要，但在突破Malt1依赖的淋巴细胞激活阈值方面则基本非必需。除NF-κB抑制因子外，Malt1还可切割一整套mRNA稳定性调控因子，包括Roquin-1、Roquin-2及Regnase-1；副半胱天冬酶失活会导致效应淋巴细胞产生过量干扰素γ（IFNγ），进而引发病理损伤。综上，本研究结果揭示了Malt1具有独特的阈值调控功能，可差异化调控淋巴细胞分化与激活通路，并证实选择性阻断副半胱天冬酶会使全身免疫向破坏性自身炎症方向偏移。实验整体设计：从经刺激（1小时与4小时）及未受刺激的T细胞中提取总RNA，设置3次生物学重复，涵盖3种基因型（Malt+/-、Malt-/-、MaltPM/-）