The CARMA3-Bcl10-MALT1 Signalosome Promotes Angiotensin II-dependent Vascular Inflammation and Atherogenesis

Abstract

The CARMA1, Bcl10, and MALT1 proteins together constitute a signaling complex (CBM signalosome) that mediates antigen-dependent activation of NF-B in lymphocytes, thereby representing a cornerstone of the adaptive immune response. Although CARMA1 is restricted to cells of the immune system, the analogous CARMA3 protein has a much wider expression pattern. Emerging evidence suggests that CARMA3 can substitute for CARMA1 in non-immune cells to assemble a CARMA3-Bcl10-MALT1 signalosome and mediate G protein-coupled receptor activation of NF-B. Here we show that one G proteincoupled receptor, the type 1 receptor for angiotensin II, utilizes this mechanism for activation of NF-B in endothelial and vascular smooth muscle cells, thereby inducing pro-inflammatory signals within the vasculature, a key factor in atherogenesis. Further, we demonstrate that Bcl10-deficient mice are protected from developing angiotensin-dependent atherosclerosis and aortic aneurysms. By uncovering a novel vascular role for the CBM signalosome, these findings illustrate that CBM-dependent signaling has functions outside the realm of adaptive immunity and impacts pathobiology more broadly than previously known.

NF-κB signaling pathways regulated by CARMA family of scaffold proteins

“…Similar defect is observed following stimulation with other GPCR ligands, such as endothelin-1 and angiotensin-II, in the absence of CARMA3 [123,128,129]. Importantly, CARMA3 is specifically required for GP-CR-induced IKK activity because CARMA3 deficiency does not affect IKK activation by other stimuli such as TNFα and lipopolysaccharide (LPS) [123].…”

CARMA3: A novel scaffold protein in regulation of NF-κB activation and diseases

“…Most importantly, when they crossed the Bcl10 -/-and ApoE -/-mice, they found that Bcl10 deficiency protected ApoE -/-mice from Ang-Ⅱ-dependent atherosclerosis and aortic aneurysms. Mechanistically, they revealed that serum levels of several pro-inflammatory mediators, which have all been implicated in the pathogenesis of atherogenesis, were also lower in ApoE -/-Bcl10 -/-mice than in ApoE -/-mice (P < 0.01) [98] . Together, these results first demonstrated that Ang Ⅱ/CARMA3/NF-κB signaling also exists and plays an important role in atherogenesis in addition to cancer.…”

“…To explore further the physiological and pathological function of CARMA3 signaling in the cardiovascular system, McAllister-Lucas et al [98] recently have revealed that CARMA3, Bcl10 and MALT1 are also expressed in vascular tissues. Consistent with previous results, Ang-Ⅱ-induced NF-κB activation was significantly impaired upon knocking down of CARMA3, Bcl10, and MALT1 in vascular smooth muscle cells.…”

“…Ang Ⅱ is a powerful hormone in the blood and regulates blood pressure [97] . In addition, it plays a crucial role in atherogenesis [98] . Atherogenesis results from vascular inflammation [99][100][101] .…”

G Protein-Coupled Receptor Dependent NF-κB Signaling in Atherogenesis

“…Following these initial studies, several groups have added to the list of GPCRs capable of harnessing the CARMA3-containing CBM signalosome. To date, however, the only receptors that have been specifically shown to utilize the signalosome in endothelial cells are those for Ang II (AGTR1), thrombin (PAR-1) and IL-8 (CXCR2) Martin et al, 2009;McAllister-Lucas et al, 2010).…”