CARD-CC complexes involving BCL10 and MALT1 are major cellular signaling hubs. They govern NF-κB activation through their scaffolding properties as well as MALT1 paracaspase function, which cleaves substrates involved in NF-κB regulation. In human lymphocytes, gain-of-function defects in this pathway lead to lymphoproliferative disorders. CARD10, the prototypical CARD-CC protein in non-hematopoietic cells, is overexpressed in several cancers and has been associated with poor prognosis. However, regulation of CARD10 remains poorly understood. Here, we identified CARD10 as the first MALT1 substrate in non-hematopoietic cells and showed that CARD10 cleavage by MALT1 at R587 dampens its capacity to activate NF-κB. Preventing CARD10 cleavage in the lung tumor A549 cell line increased basal levels of IL-6 and extracellular matrix components in vitro, and led to increased tumor growth in a mouse xenograft model, suggesting that CARD10 cleavage by MALT1 might be a built-in mechanism controlling tumorigenicity.

涉及BCL10和MALT1的CARD-CC复合物是主要的细胞信号枢纽。它们通过其支架特性和MALT1半胱天冬酶功能控制NF-κB的活化，该功能可裂解参与NF-κB调节的底物。在人类淋巴细胞中，该途径中的功能获得缺陷导致淋巴细胞增生性疾病。CARD10是非造血细胞中的典型CARD-CC蛋白，在几种癌症中过表达，并且与不良预后相关。但是，关于CARD10的法规仍然知之甚少。在这里，我们确定CARD10为非造血细胞中的第一个MALT1底物，并显示CARD10在R587处被MALT1切割削弱了其激活NF-κB的能力。预防肺肿瘤A549细胞系中的CARD10裂解可在体外增加IL-6和细胞外基质成分的基础水平，