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ABIN-2 is required for optimal activation of Erk MAP kinase in innate immune responses

Nature Immunology volume 7, pages 606–615 (2006)Cite this article

Abstract

The TPL-2 MEK kinase is essential for activation of the Erk MAP kinase pathway during innate immune responses. TPL-2 is found in complex with ABIN-2 (A20-binding inhibitor of NF-κB 2). Here, using antigen-presenting cells from ABIN-2-deficient mice, we show that ABIN-2 was required for optimal activation of Erk induced by receptors that signal via TPL-2, including Toll-like receptor 4 and tumor necrosis factor receptor 1 in macrophages, and CD40 in B cells. ABIN-2 was necessary for the maintenance of TPL-2 protein stability. In contrast, ABIN-2 deficiency did not affect agonist-induced regulation of transcription factor NF-κB. Stimulation of ABIN-2-deficient macrophages via Toll-like receptor 4 showed that different thresholds of Erk signaling were required for optimal induction of tumor necrosis factor and interleukin 1β. Thus, ABIN-2 acts to positively regulate the Erk signaling potential by stabilizing TPL-2.

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Figure 1: LPS-induced activation of NF-κB is not affected by ABIN-2 deficiency.
Figure 2: ABIN-2 does not control TNF-induced NF-κB activation.
Figure 3: ABIN-2 is not required for stimulation of NF-κB activity in B cells or T cells.
Figure 4: Activation of Erk by LPS and TNF is impaired in Tnip2−/− macrophages.
Figure 5: ABIN-2 is required for efficient activation of Erk by TLR2, TLR3 and TLR9 in macrophages.
Figure 6: Activation of Erk in Tnip2−/− B cells.
Figure 7: Retroviral reconstitution of Tnip2−/− macrophages with ABIN-2 'rescues' cells from their Erk signaling defect.
Figure 8: Regulation of Erk target genes in Tnip2−/− macrophages.
Figure 9: Optimal LPS induction of IL-1β in vivo requires ABIN-2.

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Acknowledgements

We thank T. Kitamura and P. Tsichlis for reagents; S. Beinke and B. Seddon (Division of Immune Cell Biology, NIMR) for critical reading of the manuscript; A. Garefalaki and U. Menzel (Division of Molecular Immunology, NIMR) for help with culturing targeted embryonic stem cells; M. Holman (Division of Immunoregulation, NIMR) for advice on LPS injections; and the NIMR Photographics department, NIMR Biological Services and other members of the Ley laboratory for help during the course of this work. Supported by the UK Medical Research Council and Arthritis Research Campaign (L0549 to A.S. and 16053 to F.K.).

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  1. Stamatia Papoutsopoulou and Antony Symons: These authors contributed equally to this work.

Authors and Affiliations

  1. Division of Immune Cell Biology, National Institute for Medical Research, London, NW7 1AA, UK

    Stamatia Papoutsopoulou, Antony Symons, Tharsana Tharmalingham, Monica P Belich, Victor Tybulewicz & Steven C Ley

  2. Division of Immunoregulation, National Institute for Medical Research, London, NW7 1AA, UK

    Frank Kaiser & Anne O'Garra

  3. Division of Molecular Immunology, National Institute for Medical Research, London, NW7 1AA, UK

    Dimitris Kioussis

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Supplementary information

Supplementary Fig. 1

Disruption of the Tnip2 gene in mice. (PDF 220 kb)

Supplementary Fig. 2

Survival and proliferation of B and T cells are unaffected by ABIN-2 deficiency. (PDF 198 kb)

Supplementary Fig. 3

ABIN-2 deficiency does not alter steady-state levels of Map3k8 mRNA. (PDF 215 kb)

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Papoutsopoulou, S., Symons, A., Tharmalingham, T. et al. ABIN-2 is required for optimal activation of Erk MAP kinase in innate immune responses. Nat Immunol 7, 606–615 (2006). https://doi.org/10.1038/ni1334

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