The CARMA3-Bcl10-MALT1 signalosome promotes angiotensin II-dependent vascular inflammation and atherogenesis.
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.
McAllister-Lucas
Linda M
LM
Department of Pediatrics, University of Michigan Medical School, Ann Arbor, Michigan 48109, USA.
Jin
Xiaohong
X
Gu
Shufang
S
Siu
Katy
K
McDonnell
Scott
S
Ruland
Jürgen
J
Delekta
Phillip C
PC
Van Beek
Matthew
M
Lucas
Peter C
PC
D048868:Adaptor Proteins, Signal Transducing / Q000378:metabolism*; D000804:Angiotensin II / Q000502:physiology*; D000818:Animals; D050197:Atherosclerosis / Q000209:etiology* / Q000473:pathology; D000074018:B-Cell CLL-Lymphoma 10 Protein; D001808:Blood Vessels / Q000473:pathology; D053468:CARD Signaling Adaptor Proteins / Q000378:metabolism*; D020169:Caspases / Q000378:metabolism*; D004730:Endothelium, Vascular / Q000473:pathology; D007249:Inflammation / Q000209:etiology; D051379:Mice; D018345:Mice, Knockout; D000074884:Mucosa-Associated Lymphoid Tissue Lymphoma Translocation 1 Protein; D009131:Muscle, Smooth, Vascular / Q000473:pathology; D016328:NF-kappa B / Q000378:metabolism; D009363:Neoplasm Proteins / Q000378:metabolism*; D044140:Receptor, Angiotensin, Type 1; D015398:Signal Transduction / Q000502:physiology*
D048868:Adaptor Proteins, Signal Transducing; D000074018:B-Cell CLL-Lymphoma 10 Protein; C488088:Bcl10 protein, mouse; D053468:CARD Signaling Adaptor Proteins; C498975:Card10 protein, mouse; D016328:NF-kappa B; D009363:Neoplasm Proteins; D044140:Receptor, Angiotensin, Type 1; D000804:Angiotensin II; D020169:Caspases; C498509:Malt1 protein, mouse; D000074884:Mucosa-Associated Lymphoid Tissue Lymphoma Translocation 1 Protein