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: 4.57). 08/2010; 285(34):25880-4. DOI: 10.1074/jbc.C110.109421
Source: PubMed


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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    • "The CBM complex appears to be a signaling platform, enabling the integration of effects from receptors with downstream cascades, including effects from G-protein coupled receptors [29]. The CBM complex was shown to promote angiotensin II-dependent vascular inflammation and atherogenesis, and these effects were reported to be reduced in Bcl10-deficient mice [30]. The protein A20, also known as tumor necrosis factor alpha-induced protein 3 (TNFAIP3), acts as a negative regulator of the Bcl10-CARMA interactions in both the lymphoid and nonlymphoid cells due to its effects as a ubiquitin ligase and deubiquitinase [31]. "
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    ABSTRACT: The common food additive carrageenan is a known activator of inflammation in mammalian tissues and stimulates both the canonical and noncanonical pathways of NF- κ B activation. Exposure to low concentrations of carrageenan (10 μ g/mL in the water supply) has produced glucose intolerance, insulin resistance, and impaired insulin signaling in C57BL/6 mice. B-cell leukemia/lymphoma 10 (Bcl10) is a mediator of inflammatory signals from Toll-like receptor (TLR) 4 in myeloid and epithelial cells. Since the TLR4 signaling pathway is activated in diabetes and by carrageenan, we addressed systemic and intestinal inflammatory responses following carrageenan exposure in Bcl10 wild type, heterozygous, and null mice. Fecal calprotectin and circulating keratinocyte chemokine (KC), nuclear RelA and RelB, phospho(Thr559)-NF- κ B-inducing kinase (NIK), and phospho(Ser36)-I κ B α in the colonic epithelial cells were significantly less (P < 0.001) in the carrageenan-treated Bcl10 null mice than in controls. IL-10-deficient mice exposed to carrageenan in a germ-free environment showed an increase in activation of the canonical pathway of NF- κ B (RelA) activation, but without increase in RelB or phospho-Bcl10, and exogenous IL-10 inhibited only the canonical pathway of NF- κ B activation in cultured colonic cells. These findings demonstrate a Bcl10 requirement for maximum development of carrageenan-induced inflammation and lack of complete suppression by IL-10 of carrageenan-induced inflammation.
    Mediators of Inflammation 05/2013; 2013(3):397642. DOI:10.1155/2013/397642 · 3.24 Impact Factor
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    • "CARMA3 has been reported to promote ovarian cancer cell progression [17], to increase human breast cancer cell growth and invasion [18], induce invasion of oral squamous cell carcinoma (OSCC) [23]; CARMA3 also plays an important role in atherogenesis [24] and NF-kB activation in airway epithelial cells [25]. However, the functional role remains unclear. "
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    ABSTRACT: We aimed to investigate the clinical significance of the expression of novel scaffold protein CARMA3 in non-small-cell lung cancer (NSCLC) and the biological function of CARMA3 in NSCLC cell lines. We observed moderate to high CARMA3 staining in 68.8% of 141 NSCLC specimens compared to corresponding normal tissues. The overexpression of CARMA3 was significantly correlated with TNM stage (P = 0.022) and tumor status (P = 0.013). CARMA3 upregulation also correlated with a shorter survival rate of patients of nodal status N0 (P = 0.042)as well as the expression of epidermal growth factor receptor (EGFR) (P = 0.009). In EGFR mutation positive cases, CARMA3 expression was much higher (87.5%) compared to non-mutation cases (66.1%). In addition, we observed that knockdown of CARMA3 inhibits tumor cell proliferation and invasion, and induces cell cycle arrest at the boundary between the G1 and S phase. We further demonstrated a direct link between CARMA3 and NF-κB activation. The change of biological behavior in CARMA3 knockdown cells may be NF-κB-related. Our findings demonstrated, for the first time, that CARMA3 was overexpressed in NSCLC and correlated with lung cancer progression, EGFR expression, and EGFR mutation. CARMA3 could serve as a potential companion drug target, along with NF-kB and EGFR in EGFR-mutant lung cancers.
    PLoS ONE 05/2012; 7(5):e36903. DOI:10.1371/journal.pone.0036903 · 3.23 Impact Factor
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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). "

    Atherogenesis, 01/2012; , ISBN: 978-953-307-992-9
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