CARD9 Regulation and its Role in Cardiovascular Diseases

Figures

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  Figure 1. Structural features of the CARMA proteins. CARD9, CARMA1 (CARD11), CARMA2 (CARD14), and CARMA3 (CARD10) consist of homologous N-terminal CARD and C-terminal CCD domain. In addition, CARMA1, CARMA2, and CARMA3 contain the MAGUK domain, including a PDZ, SH3 and GUK domain.

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  Figure 2. CARD9 signaling in innate immunity. As membrane-bound receptors of PRRs, including Dectin-1, Dectin-2, and Mincle, CLRs recognize β-glucans, α-mannans, and glycolipids, respectively. The ITAM of ITAM-containing receptor (Dectin-1) and ITAM-coupled receptors (Dectin-2, Mincle) can be phosphorylated by the Src family kinase to recruit and activate SYK for further phosphorylation of PKC-δ, subsequently leading to CARD9 phosphorylation. Next, CARD9 recruits BCL10 and MALT1 to form the CBM complex for the activation of MAPKs and NF-κB. The activation of NF-κB can lead to the synthesis of NLRP3 and pro-IL-1β and relayed signals from JNK and ERK pathways induce cathepsin B secretion, thus promoting NLRP3 inflammasome assembly for the production of bioactive IL-1β. In addition, cytosolic PRRs include NOD2, RAD50, and RIG-1. NOD2 recognizes intracellular bacteria and can directly activate CARD9 to activate p38 MAPK and JNK signaling pathways. RAD50 (for viral DNA) and RIG-1 (for viral RNA) can activate CARD9 and further recruit BCL10 to activate the transcription factor NF-κB. Finally, the activation of MAPKs and NF-κB contribute to the production of cytokines and chemokines.

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  Figure 3. Potential inflammatory mechanisms responsible for CARD9 signaling-induced cardiac dysfunction. Following the infiltration of innate immune cells (macrophages and neutrophils), CARD9 either activates NF-κB or forms a complex with BCL10 to phosphorylate P38 MAPK, leading to an increase of inflammatory cytokines and adhesion molecules. Then these inflammatory cytokines act on both cardiac fibroblasts and cardiomyocytes to mediate cardiac injury and remodeling and can lead to cardiac dysfunction.

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  Figure 4. CARD9 protects the heart by inhibiting apoptosis and activating autophagy. CARD9 expressed on cardiomyocytes inhibits apoptosis and promotes autophagy. In CARD9-mediated anti-apoptosis, CARD9 can bind to Apaf-1 to suppress the formation of the apoptosome complex (Apaf-1/procaspase-9), thus inhibiting caspase-9 cleavage-mediated apoptosis. In CARD9-mediated autophagy, CARD9 binds to Rubicon, preventing Rubicon binding to UVRAG for avoiding the formation of a complex with Vps16 or beclin-1/PI3KC3, since Vps16 or beclin-1/PI3KC3 is able to directly or indirectly stimulate autophagosome maturation. Then Rab7, a Rab GTPase superfamily member that promotes the maturation or fusion of the autophagosome with the lysosome, is activated to promote autophagy for the degradation of unnecessary components.