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Bcl10 and Malt1 control lysophosphatidic acid-induced NF-κB activation and cytokine production

Klemm, Stefanie, Zimmermann, Stephanie, Peschel, Christian, Mak, Tak W., Ruland, Jürgen
Proceedings of the National Academy of Sciences of the United States of America 2007 v.104 no.1 pp. 134-138
G-protein coupled receptors, antigens, fibroblasts, gene expression, interleukin-6, lymphocytes, mice, mitogen-activated protein kinase, models, phospholipids, signal transduction, transcription factor NF-kappa B
Lysophosphatidic acid (LPA) is a potent bioactive phospholipid that stimulates a variety of cellular responses by acting on cognate G protein-coupled receptors (GPCRs). There is increasing evidence that LPA signaling reprograms gene expression, but the GPCR-induced pathways connecting LPA receptor stimulation to downstream transcription factors are not well characterized. Here, we identify the adapter proteins Bcl10 and Malt1 as essential mediators of LPA-induced NF-κB activation. Both proteins were previously known to activate NF-κB in response to antigen receptor ligation on lymphocytes, but their functions in nonimmune cells are still largely undefined. By using murine embryonic fibroblasts from Bcl10- or Malt1-deficient mice as a genetic model, we report that Bcl10 and Malt1 are critically required for the degradation of IκB-α and the subsequent NF-κB induction in response to LPA stimulation. Bcl10 and Malt1 cooperate with PKCs selectively for LPA-induced NF-κB activation but are dispensable for the activation of the Jnk, p38, Erk MAP kinase, and Akt signaling pathways. In a biological readout, we demonstrate that LPA-induced IL-6 production is abolished in the absence of Bcl10. Thus, our results identify a NF-κB-inducing signaling pathway downstream of GPCRs and reveal previously unrecognized functions for Bcl10/Malt1 signaling in nonimmune cells.