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PNAS 104 (1): 139-144

Copyright © 2007 by the National Academy of Sciences.

BIOLOGICAL SCIENCES / CELL BIOLOGY

CARMA3/Bcl10/MALT1-dependent NF-{kappa}B activation mediates angiotensin II-responsive inflammatory signaling in nonimmune cells

Linda M. McAllister-Lucas*, Jürgen Ruland{dagger}, Katy Siu{ddagger}, Xiaohong Jin{ddagger}, Shufang Gu*, David S. L. Kim{ddagger}, Peter Kuffa*, Dawn Kohrt*, Tak W. Mak§, Gabriel Nuñez{ddagger}, and Peter C. Lucas{ddagger},¶

Departments of *Pediatrics and Communicable Diseases and {ddagger}Pathology, University of Michigan Medical School, Ann Arbor, MI 48109; {dagger}Third Medical Department, Technical University of Munich, Klinikum rechts der Isar, Ismaninger Strasse 22, 81675 Munich, Germany; and §Campbell Family Institute for Breast Cancer Research, Toronto, ON, Canada M5G 2C1

Edited by Michael Karin, University of California at San Diego, La Jolla, CA, and approved September 15, 2006

Received for publication March 9, 2006.

Abstract: 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-{kappa}B 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-{kappa}B, 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-{kappa}B 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-{kappa}B through ubiquitination of IKK{gamma}, the regulatory subunit of the I{kappa}B 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-{kappa}B transcription factor. These findings also uncover a function of the CARMA, Bcl10, and MALT1 proteins in cells outside the immune system.

Key Words: G protein-coupled receptor • hepatocyte • IkB kinase • inflammation • ubiquitination

Author contributions: L.M.M.-L., G.N., and P.C.L. designed research; L.M.M.-L., K.S., X.J., S.G., D.S.L.K., P.K., D.K., and P.C.L. performed research; J.R. and T.W.M. contributed new reagents/analytic tools; L.M.M.-L., K.S., X.J., S.G., D.S.L.K., P.K., D.K., G.N., and P.C.L. analyzed data; and L.M.M.-L. and P.C.L. wrote the paper.

The authors declare no conflict of interest.

This article is a PNAS direct submission.

To whom correspondence should be addressed. E-mail: plucas{at}umich.edu

© 2007 by The National Academy of Sciences of the USA

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