Thrombin-dependent NF-{kappa}B activation and monocyte/endothelial adhesion are mediated by the CARMA3·Bcl10·MALT1 signalosome.
Thrombin is a potent modulator of endothelial function and, through stimulation of NF-κB, induces endothelial expression of intracellular adhesion molecule-1 (ICAM-1) and vascular cell adhesion molecule-1 (VCAM-1). These cell surface adhesion molecules recruit inflammatory cells to the vessel wall and thereby participate in the development of atherosclerosis, which is increasingly recognized as an inflammatory condition. The principal receptor for thrombin on endothelial cells is protease-activated receptor-1 (PAR-1), a member of the G protein-coupled receptor superfamily. Although it is known that PAR-1 signaling to NF-κB depends on initial PKC activation, the subsequent steps leading to stimulation of the canonical NF-κB machinery have remained unclear. Here, we demonstrate that a complex of proteins containing CARMA3, Bcl10, and MALT1 links PAR-1 activation to stimulation of the IκB kinase complex. IκB kinase in turn phosphorylates IκB, leading to its degradation and the release of active NF-κB. Further, we find that although this CARMA3·Bcl10·MALT1 signalosome shares features with a CARMA1-containing signalosome found in lymphocytes, there are significant differences in how the signalosomes communicate with their cognate receptors. Specifically, whereas the CARMA1-containing lymphocyte complex relies on 3-phosphoinositide-dependent protein kinase 1 for assembly and activation, the CARMA3-containing endothelial signalosome functions completely independent of 3-phosphoinositide-dependent protein kinase 1 and instead relies on β-arrestin 2 for assembly. Finally, we show that thrombin-dependent adhesion of monocytes to endothelial cells requires an intact endothelial CARMA3·Bcl10·MALT1 signalosome, underscoring the importance of the signalosome in mediating one of the most significant pro-atherogenic effects of thrombin.
Cellular and Molecular Biology Graduate Program, University of Michigan Medical School, Ann Arbor, Michigan 48109, USA.
Phillip C
PC
Delekta
Ingrid J
IJ
Apel
Shufang
S
Gu
Katy
K
Siu
Yoshiyuki
Y
Hattori
Linda M
LM
McAllister-Lucas
Peter C
PC
Lucas
D048868:Adaptor Proteins, Signal Transducing / Q000378:metabolism*; D000818:Animals; D000074018:B-Cell CLL-Lymphoma 10 Protein; D053468:CARD Signaling Adaptor Proteins / Q000378:metabolism*; D020169:Caspases / Q000378:metabolism*; D042783:Endothelial Cells / Q000166:cytology*; D005786:Gene Expression Regulation; D006801:Humans; D007249:Inflammation; D051379:Mice; D009000:Monocytes / Q000166:cytology*; D000074884:Mucosa-Associated Lymphoid Tissue Lymphoma Translocation 1 Protein; D016328:NF-kappa B / Q000378:metabolism*; D009363:Neoplasm Proteins / Q000378:metabolism*; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism*; D000081382:Pyruvate Dehydrogenase Acetyl-Transferring Kinase; D044462:Receptors, Proteinase-Activated / Q000378:metabolism*; D015398:Signal Transduction; D013917:Thrombin / Q000737:chemistry* / Q000378:metabolism*; D019010:Vascular Cell Adhesion Molecule-1 / Q000378:metabolism*
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; D000081382:Pyruvate Dehydrogenase Acetyl-Transferring Kinase; D044462:Receptors, Proteinase-Activated; D019010:Vascular Cell Adhesion Molecule-1; D017346:Protein Serine-Threonine Kinases; D013917:Thrombin; D020169:Caspases; C498509:Malt1 protein, mouse; D000074884:Mucosa-Associated Lymphoid Tissue Lymphoma Translocation 1 Protein