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MALT1 directs B cell receptor–induced canonical nuclear factor-κB signaling selectively to the c-Rel subunit

Nature Immunology volume 8, pages 984–991 (2007)Cite this article

Abstract

NF-κB (Rel) transcription factors control physiological and pathological immune cell function. The scaffold proteins Bcl-10 and MALT1 couple antigen-receptor signals to the canonical NF-κB pathway and are pivotal in lymphomagenesis. Here we found that Bcl-10 and MALT1 differentially regulated B cell receptor–induced activation of RelA and c-Rel. Bcl-10 was essential for recruitment of the kinase IKK into lipid rafts for the activation of RelA and c-Rel, for blocking apoptosis and for inducing division after B cell receptor ligation. In contrast, MALT1 participated in survival signaling but was not involved in IKK recruitment or activation and was dispensable for RelA induction and proliferation. MALT1 selectively activated c-Rel to control a distinct subprogram. Our results provide mechanistic insights into B cell receptor–induced survival and proliferation signals and demonstrate the selective control of c-Rel in the canonical NF-κB pathway.

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Figure 1: Common functions for Bcl-10 and MALT1 in signaling for the survival of mature B cells.
Figure 2: Distinct functions for Bcl-10 and MALT1 after B cell activation.
Figure 3: Bcl-10 and MALT1-dependent control of survival programs in activated B cells.
Figure 4: Enforced BCL2 expression blocks apoptosis but does not restore the proliferation of BCR-stimulated Bcl10−/− B cells.
Figure 5: Differential control of BCR-induced IKK activation by Bcl-10 and MALT1.
Figure 6: Bcl-10- and MALT1-dependent regulation of IκB degradation and NF-κB DNA binding.
Figure 7: MALT1 controls the BCR-mediated nuclear translocation of c-Rel.
Figure 8: MALT1 controls the degradation of IκB molecules that are bound to c-Rel.

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Acknowledgements

We thank F. Greten, T. Mak and M. Reth for scientific discussions; M. Schiemann for cell sorting; G. Häcker (Technical University Munich) for vav-Bcl2 transgenic mice; V. Dixit (Genentech) for anti-MALT1; and E. Muggleton for critically reading the manuscript. Supported by Deutsche Forschungsgemeinschaft (Sonderforschungsbereiche grants) and Deutsche Krebshilfe (Max-Eder-Program grant to J.R).

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Authors and Affiliations

  1. Third Medical Department, Technical University of Munich, Klinikum rechts der Isar, Munich, 81675, Germany

    Uta Ferch, Christian Meyer zum Büschenfelde, Andreas Gewies, Christian Peschel & Jürgen Ruland

  2. Institute of Toxicology, The GSF-Research Center for Environment and Health, Neuherberg, D-85764, Germany

    Elmar Wegener & Daniel Krappmann

  3. Institute for Pathology, The GSF-Research Center for Environment and Health, Neuherberg, D-85764, Germany

    Sandra Rauser

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Contributions

J.R. designed and coordinated the study, analyzed data and wrote the paper; U.F. coordinated the study, did experiments, analyzed data and contributed to manuscript writing; D.K. and C.P. contributed intellectual input; and C.M.z.B., A.G., E.W. and S.R. cooperated in experiments and data analysis.

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Correspondence to Jürgen Ruland.

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Ferch, U., Büschenfelde, C., Gewies, A. et al. MALT1 directs B cell receptor–induced canonical nuclear factor-κB signaling selectively to the c-Rel subunit. Nat Immunol 8, 984–991 (2007). https://doi.org/10.1038/ni1493

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