Editors' ChoiceCell Biology

Connecting GPCRs to NF-κB

STKE  09 Jan 2007:
Vol. 2007, Issue 368, pp. tw12
DOI: 10.1126/stke.3682007tw12

Many different kinds of receptors can activate the proinflammatory transcriptional regulator NF-κB. NF-κB is maintained in an inactive state in the cytosol through its interaction with the protein IκB, and activation involves stimulation of the IκB kinase (IKK). In T and B cells, a signaling adaptor complex consisting of CARMA1 [caspase recruitment domain (CARD) 11], Bcl10, and MALT1 connects the receptor-induced activation of protein kinase C (PKC) to activation of IKK and NF-κB. Three groups report a similar signaling adaptor complex in the transmission of signals from G protein-coupled receptors (GPCRs) to NF-κB activation. NF-κB activation plays a pathophysiological role in many types of liver disease and appears to be mediated by the increased activity of angiotensin II (Ang II) at the type I Ang II receptor. McAllister-Lucas et al. show that the CARMA3 [caspase recruitment domain (CARD) 10], a scaffolding protein related to CARMA1, which is found in immune cells, is present in many tissues, including liver, along with Bcl10 and MALT1. Through the analysis of dominant-negative mutants, knockout mouse cells, and RNA interference studies, McAllister-Lucas et al. show that, similar to activation by immune receptors, Ang II stimulates NF-κB activation by signaling through a CARMA3-Bcl10-MALT1 complex. In each study, activation of NF-κB by tumor necrosis factor α, which acts through a different type of receptor, was unaffected. Two additional groups report that the GPCRs activated by lysophosphatidic acid (LPA) (Wang et al. and Klemm et al.) or endothelin-1 (Wang et al.) also signal through Bcl10 and MALT1 to activate NF-κB. Experiments with mouse embryo fibroblasts from mice deficient in Bcl10 (Wang et al. and Klemm et al.) or MALT1 (Klemm et al.) show that these two proteins were essential for the activation of NF-κB by LPA. From the combined studies, Bcl10 and MALT1 were not required for activation of various members of the mitogen-activated protein kinase family, including p38, JNK, and ERK, nor were they required for activation of the kinase Akt. Both groups showed that pharmacological studies suggested that PKC activation was required for GPCR-mediated NF-κB activation, whereas phosphatidylinositol 3-kinase activity was not.

L. M. McAllister-Lucas, J. Ruland, K. Siu, X. Jin. S. Gu, D. S. L. Kim, P. Kuffa, D. Kohrt, T. W. Mak, G. Nuñez, P. C. Lucas, CARMA3/Bcl10/MALT1-dependent NF-κB activation mediates angiotensin II-responsive inflammatory signaling in nonimmune cells. Proc. Natl. Acad. Sci. U.S.A. 104, 139-144 (2007). [Abstract] [Full Text]

D. Wang, Y. You, P.-C. Lin, L. Xue, S. W. Morris, H. Zeng, R. Wen, X. Lin, Bcl10 plays a critical role in NF-κB activation induced by G protein-coupled receptors. Proc. Natl. Acad. Sci. U.S.A. 104, 145-150 (2007). [Abstract] [Full Text]

S. Klemm, S. Zimmermann, C. Peschel, T. W. Mak, J. Ruland, Bcl10 and Malt1 control lysophosphatidic acid-induced NF-κB activation and cytokine production. Proc. Natl. Acad. Sci. U.S.A. 104, 134-138 (2007). [Abstract] [Full Text]