Novartis Institutes for BioMedical Research, Novartis Campus, Basel, Switzerland.
Institute of Molecular Toxicology and Pharmacology, Research Unit Cellular Signal Integration, Helmholtz Zentrum München - German Research Center for Environmental Health, Neuherberg, Germany.
Biochem Biophys Res Commun. 2018 Nov 17;506(1):48-52. doi: 10.1016/j.bbrc.2018.10.029. Epub 2018 Oct 15.
The MALT1 (Mucosa associated lymphoid tissue lymphoma translocation protein 1) paracaspase couples antigen receptors on lymphocytes to downstream signaling events. Activation of MALT1 is known to involve stimulus-dependent CBM complex formation, that is, the recruitment of BCL10-bound MALT1 to a CARD-Coiled Coil protein. Beyond this canonical, CBM-dependent mechanism of MALT1 activation, recent studies suggest that MALT1 protease activity may be triggered by alternative mechanisms. For instance, the E3-ligase TRAF6 can activate MALT1 proteolytic function and induce MALT1 auto-cleavage. However, the interplay between CBM and TRAF6 with regard to MALT1 activation has remained incompletely elucidated. Here, by generating CRISPR/Cas9-derived knock-out Jurkat T-cells, we show that TRAF6 was dispensable for CARD11/BCL10-dependent MALT1 activation upon T-cell stimulation. However, ectopically-expressed TRAF6 could induce MALT1 activity in Jurkat T-cells devoid of either CARD11 or BCL10. These data provide unequivocal evidence that TRAF6-mediated MALT1 activation does not require the upstream scaffold CARD11 or the interaction between MALT1 and BCL10. Thus, TRAF6 may be part of a previously unidentified non-canonical pathway that triggers MALT1 protease activity independently of canonical CBM signalosomes.
MALT1（粘膜相关淋巴组织淋巴瘤易位蛋白 1）颗粒酶偶联淋巴细胞上的抗原受体与下游信号事件。已知 MALT1 的激活涉及刺激依赖性 CBM 复合物的形成，即结合 BCL10 的 MALT1 募集到 CARD-卷曲螺旋蛋白。除了这种经典的、依赖于 CBM 的 MALT1 激活机制外，最近的研究表明，MALT1 蛋白酶活性可能由替代机制触发。例如，E3 连接酶 TRAF6 可以激活 MALT1 蛋白水解功能并诱导 MALT1 自切割。然而，关于 CBM 和 TRAF6 对 MALT1 激活的相互作用仍然不完全清楚。在这里，通过生成 CRISPR/Cas9 衍生的敲除 Jurkat T 细胞，我们表明 TRAF6 对于 T 细胞刺激时 CARD11/BCL10 依赖性 MALT1 激活是可有可无的。然而，外源性表达的 TRAF6 可以在缺乏 CARD11 或 BCL10 的 Jurkat T 细胞中诱导 MALT1 活性。这些数据提供了明确的证据表明，TRAF6 介导的 MALT1 激活不需要上游支架 CARD11 或 MALT1 与 BCL10 之间的相互作用。因此，TRAF6 可能是一种以前未识别的非经典途径的一部分，该途径独立于经典的 CBM 信号体触发 MALT1 蛋白酶活性。
