Bcl10 and Malt1 control lysophosphatidic acid-induced NF-kappaB activation and cytokine production.
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-kappaB activation. Both proteins were previously known to activate NF-kappaB 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 IkappaB-alpha and the subsequent NF-kappaB induction in response to LPA stimulation. Bcl10 and Malt1 cooperate with PKCs selectively for LPA-induced NF-kappaB 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-kappaB-inducing signaling pathway downstream of GPCRs and reveal previously unrecognized functions for Bcl10/Malt1 signaling in nonimmune cells.
Klemm
Stefanie
S
Third Medical Department, Technical University of Munich, Klinikum Rechts der Isar, Ismaninger Strasse 22, 81675 Munich, Germany.
Zimmermann
Stephanie
S
Peschel
Christian
C
Mak
Tak W
TW
Ruland
Jürgen
J
D048868:Adaptor Proteins, Signal Transducing / Q000502:physiology*; D000818:Animals; D000074018:B-Cell CLL-Lymphoma 10 Protein; D020169:Caspases / Q000502:physiology*; D002478:Cells, Cultured; D015850:Interleukin-6 / Q000096:biosynthesis*; D008246:Lysophospholipids / Q000494:pharmacology*; D051379:Mice; D000074884:Mucosa-Associated Lymphoid Tissue Lymphoma Translocation 1 Protein; D016328:NF-kappa B / Q000378:metabolism*; D009363:Neoplasm Proteins / Q000502:physiology*; D011493:Protein Kinase C / Q000502:physiology; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D015398:Signal Transduction; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism
D048868:Adaptor Proteins, Signal Transducing; D000074018:B-Cell CLL-Lymphoma 10 Protein; C488088:Bcl10 protein, mouse; D015850:Interleukin-6; D008246:Lysophospholipids; D016328:NF-kappa B; D009363:Neoplasm Proteins; D051057:Proto-Oncogene Proteins c-akt; D011493:Protein Kinase C; D048051:p38 Mitogen-Activated Protein Kinases; D020169:Caspases; C498509:Malt1 protein, mouse; D000074884:Mucosa-Associated Lymphoid Tissue Lymphoma Translocation 1 Protein; C032881:lysophosphatidic acid