Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, MA 02115, USA; Program in Cellular and Molecular Medicine, Boston Children's Hospital, Boston, MA 02115, USA.
Mol Cell. 2013 Sep 26;51(6):766-79. doi: 10.1016/j.molcel.2013.08.032.
The CARMA1/Bcl10/MALT1 (CBM) signalosome mediates antigen receptor-induced NF-κB signaling to regulate multiple lymphocyte functions. While CARMA1 and Bcl10 contain caspase recruitment domains (CARDs), MALT1 is a paracaspase with structural similarity to caspases. Here we show that the reconstituted CBM signalosome is a helical filamentous assembly in which substoichiometric CARMA1 nucleates Bcl10 filaments. Bcl10 filament formation is a highly cooperative process whose threshold is sensitized by oligomerized CARMA1 upon receptor activation. In cells, both cotransfected CARMA1/Bcl10 complex and the endogenous CBM signalosome are filamentous morphologically. Combining crystallography, nuclear magnetic resonance, and electron microscopy, we reveal the structure of the Bcl10 CARD filament and the mode of interaction between CARMA1 and Bcl10. Structure-guided mutagenesis confirmed the observed interfaces in Bcl10 filament assembly and MALT1 activation in vitro and NF-κB activation in cells. These data support a paradigm of nucleation-induced signal transduction with threshold response due to cooperativity and signal amplification by polymerization.
CARMA1/Bcl10/MALT1（CBM）信号小体介导抗原受体诱导的 NF-κB 信号转导，以调节多种淋巴细胞功能。虽然 CARMA1 和 Bcl10 含有半胱天冬酶募集结构域（CARD），但 MALT1 是一种具有与半胱天冬酶相似结构的副半胱天冬酶。在这里，我们表明，重建的 CBM 信号小体是一种螺旋丝状组装体，其中亚化学计量的 CARMA1 引发 Bcl10 丝的形成。Bcl10 丝形成是一个高度协作的过程，其阈值在受体激活时被寡聚化的 CARMA1 敏化。在细胞中，转染的 CARMA1/Bcl10 复合物和内源性 CBM 信号小体都是丝状形态。结合晶体学、核磁共振和电子显微镜，我们揭示了 Bcl10 CARD 丝的结构以及 CARMA1 和 Bcl10 之间的相互作用模式。结构引导的突变分析证实了在体外 Bcl10 丝组装和 MALT1 激活以及细胞中 NF-κB 激活中观察到的界面。这些数据支持了由于协同作用和聚合的信号放大而导致的引发诱导的信号转导的范例，具有阈值响应。
