L-CBM signaling in lymphocyte development and function

Figures & data

Figure 1 L-CBM complex and M-CBM complex.

Notes: Structure of CARMA1, CARD9, BCL10 and MALT1 are shown.
Abbreviations: L-CBM, lymphoid-CARMA1-BCL10-MALT1; M-CBM, myeloid-CARD9-BCL10-MALT1; CARD, caspase recruitment domain; C-C, coiled-coil domain; PRD, protein-kinase-C-regulated domain; PDZ, PSD95, DLGA and ZO1 homology domain; SH3, Src-homology 3 domain; GUK, guanylate kinase domain; MAGUK, membrane-associated guanylate kinase; S/T-rich, serine/threonine-rich domain; DD, death domain; Ig, immunoglobulin-like domain.

Figure 2 Schematic signaling pathway mediated by the L-CBM complex in T and B lymphocytes.

Notes: The L-CBM complex acts in the canonical NF-κB (p65/p50, cRel/p50) activation pathway mediated by IKKβ downstream of TCRs and BCRs. L-CBM also controls the JNK, particularly JNK2, activation pathway through antigen receptors, leading to c-JUN activation. Upon antigen receptor stimulation, PKCθ in T cells and PKCβ in B cells phosphorylate CARMA1 in the PRD region (see Figure 4), enabling the formation and membrane recruitment of the L-CBM complex. IKKβ positively and negatively regulates L-CBM signaling. These signaling events are regulated by the recruitment of signaling components to specific membrane domains, such as lipid rafts, after receptor triggering. In MZ B cells, L-CBM mediates signals for canonical NF-κB activation through TLR4-Myd88. L-CBM also mediates signals for noncanonical NF-κB (RelB/p52) activation mediated by NIK and IKKα downstream of the BAFF receptor (BAFF-R), which regulates the survival of MZ B cells.

Figure 3 Schematic signaling pathway mediated by the L-CBM complex in NK cells.

Notes: The L-CBM complex acts in the canonical NF-κB activation pathway through activating NK cell receptors (NKR) such as Ly49H, Ly49D, NK1.1, NKG2D, FcγRIII, etc. L-CBM might regulate MAPK activation through activating NKR, although this notion remains controversial. Similar to T cells, PKCθ activity is required for NF-κB activation through activating NKR. IL-18R-MyD88-mediated NF-κB activation does not require L-CBM in NK cells. While the PKCθ-L-CBM signaling is essential to cytokine/chemokine production, it is not necessary for cytotoxicity.

Figure 4 Regulatory phosphorylation sites, polyubiquitylation sites (Ub), proteolytic cleavage sites, and functional domains in L-CBM molecules.

Notes: The figure refers to the human CARMA1, BCL10, and MALT1 protein unless otherwise indicated. Blue text denotes positive regulatory sites and red text denotes negative regulation sites. L298Q (in mouse) and L808P indicate loss-of-function point mutations found in CARMA1.
Abbreviations: PRD, PKC-regulated domain; 5S, five serines; CNS, COP9 signalosome.