Article

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

Department of Pediatrics, University of Michigan Medical School, Ann Arbor, Michigan 48109, USA.
Journal of Biological Chemistry (Impact Factor: 4.6). 08/2010; 285(34):25880-4. DOI: 10.1074/jbc.C110.109421
Source: PubMed

ABSTRACT The CARMA1, Bcl10, and MALT1 proteins together constitute a signaling complex (CBM signalosome) that mediates antigen-dependent activation of NF-kappaB 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-kappaB. Here we show that one G protein-coupled receptor, the type 1 receptor for angiotensin II, utilizes this mechanism for activation of NF-kappaB 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.

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    • "This effect of Ang II infusion is generally accepted to be the result of its direct pro-inflammatory effects on the vessel wall, which conspires with hyperlipidemia to cause accelerated atherogenesis. We tested the role of the CBM signalosome by crossing ApoE -/-and Bcl10 -/-mice to generate a double knock-out line (McAllister-Lucas et al., 2010). "
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