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CARMA3/Bcl10/MALT1-dependent NF-κB activation mediates angiotensin II-responsive inflammatory signaling in nonimmune cells

McAllister-Lucas, Linda M., Ruland, Jürgen, Siu, Katy, Jin, Xiaohong, Gu, Shufang, Kim, David S.L., Kuffa, Peter, Kohrt, Dawn, Mak, Tak W., Nuñez, Gabriel, Lucas, Peter C.
Proceedings of the National Academy of Sciences of the United States of America 2007 v.104 no.1 pp. 139-144
G-protein coupled receptors, RNA interference, angiotensin II, cytokines, extracellular matrix, gene targeting, hepatocytes, immune system, liver, liver cirrhosis, mice, mutants, signal transduction, tissue repair, transcription factor NF-kappa B, ubiquitination
Angiotensin II (Ang II) is a peptide hormone that, like many cytokines, acts as a proinflammatory agent and growth factor. After injury to the liver, the hormone assists in tissue repair by stimulating hepatocytes and hepatic stellate cells to synthesize extracellular matrix proteins and secrete secondary cytokines and by stimulating myofibroblasts to proliferate. However, under conditions of chronic liver injury, all of these effects conspire to promote pathologic liver fibrosis. Much of this effect of Ang II results from activation of the proinflammatory NF-κB transcription factor in response to stimulation of the type 1 Ang II receptor, a G protein-coupled receptor. Here, we characterize a previously undescribed signaling pathway mediating Ang II-dependent activation of NF-κB, which is composed of three principal proteins, CARMA3, Bcl10, and MALT1. Blocking the function of any of these proteins, through the use of either dominant-negative mutants, RNAi, or gene targeting, effectively abolishes Ang II-dependent NF-κB activation in hepatocytes. In addition, Bcl10⁻/⁻ mice show defective hepatic cytokine production after Ang II treatment. Evidence also is presented that this pathway activates NF-κB through ubiquitination of IKKγ, the regulatory subunit of the IκB kinase complex. These results elucidate a concrete series of molecular events that link ligand activation of the type 1 Ang II receptor to stimulation of the NF-κB transcription factor. These findings also uncover a function of the CARMA, Bcl10, and MALT1 proteins in cells outside the immune system.