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Control of RelB during dendritic cell activation integrates canonical and noncanonical NF-κB pathways

Nature Immunology volume 13, pages 1162–1170 (2012)Cite this article

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Abstract

The NF-κB protein RelB controls dendritic cell (DC) maturation and may be targeted therapeutically to manipulate T cell responses in disease. Here we report that RelB promoted DC activation not as the expected RelB-p52 effector of the noncanonical NF-κB pathway, but as a RelB-p50 dimer regulated by canonical IκBs, IκBα and IκBɛ. IκB control of RelB minimized spontaneous maturation but enabled rapid pathogen-responsive maturation. Computational modeling of the NF-κB signaling module identified control points of this unexpected cell type–specific regulation. Fibroblasts that we engineered accordingly showed DC-like RelB control. Canonical pathway control of RelB regulated pathogen-responsive gene expression programs. This work illustrates the potential utility of systems analyses in guiding the development of combination therapeutics for modulating DC-dependent T cell responses.

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Figure 1: A MEF-based kinetic model does not account for RelB regulation in DCs.
Figure 2: IκBα binding RelB-p50 limits spontaneous DC maturation.
Figure 3: RelB-p50 is rapidly activated during TLR-mediated DC maturation.
Figure 4: Determinants of RelB's responsiveness to canonical signals.
Figure 5: RelB regulates DC activation markers and inflammatory mediators.
Figure 6: RelB may mediate cRel functions in DCs.

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Acknowledgements

We thank Z. Tao and G. Ghosh (University of California San Diego) for plasmids and recombinant proteins, S. Basak, A. Wu, P. Loriaux, R. Tsui for computational modeling advice, and C. Brown and M. Karin (University of California San Diego) for Traf3−/− embryos. This study was supported by GM085763 (A.H.), GM071573 (A.H.), AI090935 (A.H.), GM085325 (J.P.) and AI081923 (E.I.Z.).

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Author notes

  1. Jeffrey D Kearns

    Present address: Present address: Merrimack Pharmaceuticals, Cambridge, Massachusetts, USA.,

Authors and Affiliations

  1. Department of Chemistry and Biochemistry and San Diego Center for Systems Biology, Signaling Systems Laboratory, University of California, San Diego, La Jolla, California, USA.,

    Vincent F-S Shih, Jeremy Davis-Turak, Jenny Q Huang, Jeffrey D Kearns, Tony Yu, Riku Fagerlund, Masataka Asagiri & Alexander Hoffmann

  2. Division of Biological Sciences, University of California, San Diego, La Jolla, California, USA.,

    Monica Macal & Elina I Zuniga

  3. San Diego Supercomputer Center, University of California, San Diego, La Jolla, California, USA.,

    Julia Ponomarenko

  4. Innovation Center for Immunoregulation and Therapeutics, Graduate School of Medicine, Kyoto University, Yoshida-Konoe, Sakyoku, Kyoto, Japan

    Masataka Asagiri

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Contributions

V.F.-S.S. and A.H. designed the study. V.F.-S.S. and M.M. carried out all experimental work with assistance from J.Q.H., T.Y., R.F. and M.A., and guidance from E.I.Z. and A.H. J.D.-T. and J.D.K. carried out the computational modeling work and J.P. the bioinformatic analysis. V.F.-S.S. and A.H. wrote the manuscript with contributions from all authors.

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Correspondence to Alexander Hoffmann.

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Shih, VS., Davis-Turak, J., Macal, M. et al. Control of RelB during dendritic cell activation integrates canonical and noncanonical NF-κB pathways. Nat Immunol 13, 1162–1170 (2012). https://doi.org/10.1038/ni.2446

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