Structural Architecture of the CARMA1/Bcl10/MALT1 Signalosome: Nucleation-Induced Filamentous Assembly

The CARMA1/Bcl10/MALT1 (CBM) signalosome mediates antigen receptor-induced NF-κB signaling toregulate 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 cotransfectedCARMA1/Bcl10 complex and the endogenous CBMsignalosome are filamentous morphologically.Combining crystallography, nuclear magnetic resonance, and electron microscopy, we reveal thestructure of the Bcl10 CARD filament and themodeof interaction between CARMA1 and Bcl10.Structure-guided mutagenesis confirmed the observed interfaces in Bcl10 filament assembly and MALT1 activation invitro and NF-κB activation in cells. These data support a paradigm of nucleation-induced signal transduction with threshold response due tocooperativity and signal amplification by polymerization.