Uncoupling Malt1 Threshold Function from Paracaspase Activity Results in Destructive Autoimmune Inflammation
Uncoupling Malt1 Threshold Function from Paracaspase Activity Results in Destructive Autoimmune Inflammation
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DOI：
10.1016/j.celrep.2014.10.044
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发表时间：
2014-11-20
期刊：
影响因子：
8.8
通讯作者：
Ruland, Juergen
中科院分区：
文献类型：
--
作者：
Gewies, Andreas;Gorka, Oliver;Ruland, Juergen
paracaspase Malt 1是抗原受体信号传导的中心调节因子，在人类淋巴瘤中经常发生突变。作为支架，它组装用于NF-κ B活化的蛋白复合物，并且其蛋白水解结构域切割负NF-κ B调节物用于信号执行。然而，Malt 1蛋白酶的生理功能尚不清楚。我们证明，有针对性的Malt 1-paracaspase失活诱导一个致命的炎症综合征与淋巴细胞依赖性神经退行性变在体内。半胱天冬酶活性对于调节性T细胞（Treg）和先天性类B细胞发育是必不可少的，但它在很大程度上不适于克服Malt 1依赖的淋巴细胞活化阈值。除了NF-κ B抑制剂外，Malt 1还切割一整套mRNA稳定性调节因子，包括Roquin-1、Roquin-2和Regnase-1，paracaspase失活导致效应淋巴细胞产生过量干扰素γ（IFN γ），从而导致病理。总之，我们的研究结果揭示了Malt 1的不同阈值和调节功能，这些功能差异性地控制淋巴细胞分化和活化途径，并证明选择性paracaspase阻断使全身免疫向破坏性自身炎症倾斜。
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-kappa B activation, and its proteolytic domain cleaves negative NF-kappa B 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-kappa B 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 (IFN gamma) 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.