PDF(Pubmed)
Abstract：
CARD-BCL10-MALT1 (CBM) signalosomes connect distal signaling of innate and adaptive immune receptors to proximal signaling pathways and immune activation. Four CARD scaffold proteins (CARD9, 10, 11, 14) can form seeds that nucleate the assembly of BCL10-MALT1 filaments in a cell- and stimulus-specific manner. MALT1 (also known as PCASP1) serves a dual function within the assembled CBM complexes. By recruiting TRAF6, MALT1 acts as a molecular scaffold that initiates IκB kinase (IKK)/NF-κB and c-Jun N-terminal kinase (JNK)/AP-1 signaling. In parallel, proximity-induced dimerization of the paracaspase domain activates the MALT1 protease which exerts its function by cleaving a set of specific substrates. While complete MALT1 ablation leads to immune deficiency, selective destruction of either scaffolding or protease function provokes autoimmune inflammation. Thus, balanced MALT1-TRAF6 recruitment and MALT1 substrate cleavage are critical to maintain immune homeostasis and to promote optimal immune activation. Further, MALT1 protease activity drives the survival of aggressive lymphomas and other non-hematologic solid cancers. However, little is known about the relevance of the cleavage of individual substrates for the pathophysiological functions of MALT1. Unbiased serendipity, screening and computational predictions have identified and validated ~20 substrates, indicating that MALT1 targets a quite distinct set of proteins. Known substrates are involved in CBM auto-regulation (MALT1, BCL10 and CARD10), regulation of signaling and adhesion (A20, CYLD, HOIL-1 and Tensin-3), or transcription (RelB) and mRNA stability/translation (Regnase-1, Roquin-1/2 and N4BP1), indicating that MALT1 often targets multiple proteins involved in similar cellular processes. Here, we will summarize what is known about the fate and functions of individual MALT1 substrates and how their cleavage contributes to the biological functions of the MALT1 protease. We will outline what is needed to better connect critical pathophysiological roles of the MALT1 protease with the cleavage of distinct substrates.
摘要：
CARD-BCL10-MALT1（CBM）信号体将先天和适应性免疫受体的远端信号连接到近端信号通路和免疫激活。四种CARD支架蛋白（CARD9，10，11，14）可以形成种子，这些种子以细胞和刺激特异性方式使BCL10-MALT1丝的组装成核。MALT1（也称为PCASP1）在组装的CBM复合物中具有双重功能。通过募集TRAF6，MALT1充当启动IκB激酶（IKK）/NF-κB和c-JunN末端激酶（JNK）/AP-1信号传导的分子支架。并行,邻近诱导的paracaspase结构域的二聚化激活MALT1蛋白酶，该蛋白酶通过切割一组特定底物来发挥其功能。虽然完全MALT1消融会导致免疫缺陷，支架或蛋白酶功能的选择性破坏会引发自身免疫性炎症。因此，平衡的MALT1-TRAF6募集和MALT1底物裂解对于维持免疫稳态和促进最佳免疫激活至关重要。Further,MALT1蛋白酶活性驱动侵袭性淋巴瘤和其他非血液实体癌的存活。然而,关于单个底物的裂解与MALT1的病理生理功能的相关性知之甚少。无偏见的偶然性，筛选和计算预测已经确定并验证了约20种底物，这表明MALT1靶向一组截然不同的蛋白质。已知的底物涉及CBM自动调节（MALT1，BCL10和CARD10），信号和粘附的调节(A20，CYLD，HOIL-1和Tensin-3），或转录（RelB）和mRNA稳定性/翻译（Regnase-1，Roquin-1/2和N4BP1），这表明MALT1通常靶向参与类似细胞过程的多种蛋白质。这里,我们将总结已知的关于单个MALT1底物的命运和功能以及它们的切割如何有助于MALT1蛋白酶的生物学功能。我们将概述如何更好地将MALT1蛋白酶的关键病理生理作用与不同底物的裂解联系起来。
