MALT1 Protease Activity Is Required for Innate and Adaptive Immune Responses

CARMA-BCL10-MALT1 signalosomes play important roles in antigen receptor signaling and other pathways. Previous studies have suggested that as part of this complex, MALT1 functions as both a scaffolding protein to activate NF-κB through recruitment of ubiquitin ligases, and as a protease to cleave and inactivate downstream inhibitory signaling proteins. However, our understanding of the relative importance of these two distinct MALT1 activities has been hampered by a lack of selective MALT1 protease inhibitors with suitable pharmacologic properties. To fully investigate the role of MALT1 protease activity, we generated mice homozygous for a protease-dead mutation in MALT1. We found that some, but not all, MALT1 functions in immune cells were dependent upon its protease activity. Protease-dead mice had defects in the generation of splenic marginal zone and peritoneal B1 B cells. CD4+ and CD8+ T cells displayed decreased T cell receptor-stimulated proliferation and IL-2 production while B cell receptor-stimulated proliferation was partially dependent on protease activity. In dendritic cells, stimulation of cytokine production through the Dectin-1, Dectin-2, and Mincle C-type lectin receptors was also found to be partially dependent upon protease activity. In vivo, protease-dead mice had reduced basal immunoglobulin levels, and showed defective responses to immunization with T-dependent and T-independent antigens. Surprisingly, despite these decreased responses, MALT1 protease-dead mice, but not MALT1 null mice, developed mixed inflammatory cell infiltrates in multiple organs, suggesting MALT1 protease activity plays a role in immune homeostasis. These findings highlight the importance of MALT1 protease activity in multiple immune cell types, and in integrating immune responses in vivo.CARMA-BCL10-MALT1信号小体 (signalosomes) 在抗原受体信号转导及其他通路中发挥重要作用。既往研究表明，作为该复合物的组成部分，MALT1同时兼具双重功能：一方面作为支架蛋白，通过招募泛素连接酶 (ubiquitin ligases) 激活NF-κB通路；另一方面作为蛋白酶，切割并灭活下游的抑制性信号蛋白。然而，由于缺乏具备合适药理学特性的选择性MALT1蛋白酶抑制剂，我们对这两种截然不同的MALT1活性的相对重要性的认知一直受到限制。为全面探究MALT1蛋白酶活性的功能，我们构建了携带MALT1蛋白酶失活纯合突变的小鼠模型。研究发现，免疫细胞中部分（而非全部）MALT1功能依赖于其蛋白酶活性。蛋白酶失活型小鼠在脾脏边缘区B细胞及腹膜腔B1 B细胞的生成过程中存在缺陷。CD4+及CD8+ T细胞的T细胞受体 (T cell receptor) 刺激增殖能力与白细胞介素-2 (IL-2) 分泌水平均出现下降；而B细胞受体 (B cell receptor) 刺激的细胞增殖则部分依赖于蛋白酶活性。在树突状细胞中，通过Dectin-1、Dectin-2及Mincle C型凝集素受体 (C-type lectin receptors) 刺激细胞因子产生的过程，同样被发现部分依赖于蛋白酶活性。在体实验中，蛋白酶失活型小鼠的基础免疫球蛋白水平降低，且对T细胞依赖性抗原 (T-dependent antigens) 与T细胞非依赖性抗原 (T-independent antigens) 的免疫应答存在缺陷。令人意外的是，尽管存在上述应答减弱的情况，MALT1蛋白酶失活型小鼠（而非MALT1基因敲除小鼠）在多个器官中出现了混合性炎症细胞浸润，这表明MALT1蛋白酶活性在免疫稳态 (immune homeostasis) 中发挥着重要作用。本研究结果凸显了MALT1蛋白酶活性在多种免疫细胞类型以及体内免疫应答整合过程中的重要性。