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TAB2 controls a TAK1-independent cell death checkpoint at the level of TNFR1 complex II in the TNF pathway

Cell Death & Differentiation volume 33, pages 64–76 (2026)Cite this article

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Abstract

Tumor necrosis factor (TNF) signaling determines the cell’s fate by promoting either survival or cell death via apoptosis, necroptosis or pyroptosis. Excessive or chronic cell death by TNF was shown to drive inflammatory pathologies, highlighting the importance of the mechanisms that normally block TNF cytotoxicity. This study investigates the role of TAB2, an adaptor protein traditionally linked to TAK1 activation in the TNF pathway. Contrary to expectations, TAB2 deficiency did not impair TAK1-dependent NF-κB or MAPK signaling, nor did it affect TAK1- and IKK-dependent inhibitory phosphorylation of RIPK1 in TNFR1 complex I, indicating that TAK1 remains functional in absence of TAB2. Still, TAB2 deficiency switches the TNF response from survival to apoptosis, demonstrating a crucial TAK1-independent pro-survival function of TAB2 in the pathway. This switch was absent in TAB3-deficient conditions, highlighting a non-redundant function of TAB2. We show that TAB2 is an integral part of TNFR1 complex II, limiting the abundance of the cytotoxic complex through direct association. The ubiquitin-binding NZF domain of TAB2 is critical for this function as cells expressing a NZF-deficient mutant switched the TNF response towards apoptosis, while not affecting TAK1-mediated signaling. Moreover, we found that the NZF domain of TAB2 also represses TNF-mediated necroptosis in conditions of Caspase-8 inhibition, thereby showing that TAB2 represses two different cell death modalities in the TNF pathway by limiting the abundance of two variations of the cytotoxic complex II. Together, our results reveal the existence of a new cell death checkpoint in the TNF pathway that is controlled by TAB2, through a mechanism independent of its established function in TAK1 recruitment and activation.

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Fig. 1: TAB2 deficiency switches the TNF response to apoptosis.
Fig. 2: The cytoprotective role of TAB2 is independent of TAK1.
Fig. 3: TAB2 protects cells from TNF-induced apoptosis at the level of Complex II.
Fig. 4: TAB2 limits Complex II formation by binding to its associated K63-ubiquitin chains.
Fig. 5: TAB2 deficiency sensitizes cells to TNF-induced necroptosis.

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Data availability

All data generated or analysed during this study are included in this published article [and its supplementary information files]. Any data generated for this story can be requested from the corresponding author.

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Acknowledgements

We are grateful to Dr. K. Augustyns (University of Antwerp, Belgium) for the synthesis of Nec-1s that was used throughout the project. We thank Dr. J. Silke and N. Silke (WEHI, Australia) for kindly providing the cIAP1/2-/- and Tak1ΔEx2/ΔEx2 cells.

Funding

Research in the group of MJMB is financially supported by the Vlaams Instituut voor Biotechnologie (VIB); Ghent University (iBOF ATLANTIS grant 01IB3920 (in consortium with PV) and GOA grant 01G00123); the Fonds voor Wetenschappelijk Onderzoek Vlaanderen (FWO) (research grants 3G046420, G0A7L24N and EOS grant G0I5722N (in consortium with PV)) and the Flemish Government (Methusalem BOF22/MET_V/007, attributed to PV). Research in the lab of PV is additionally supported by FWO grants G.0B96.20 N and G.0A93.22 N and by a grant (F/2020/1505) from the Foundation against Cancer. TD, JH and DP are paid by postdoctoral fellowships from the FWO (respectively: 1248624 N, 1270825 N, 1269425 N).

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Authors and Affiliations

  1. VIB Center for Inflammation Research, 9052, Ghent, Belgium

    Tom Delanghe, Mike Vadi, Annelore Haems, Lisa Wijns, Inge Bruggeman, Jon Huyghe, Dario Priem, Peter Vandenabeele & Mathieu JM Bertrand

  2. Department of Biomedical Molecular Biology, Ghent University, 9052, Ghent, Belgium

    Tom Delanghe, Mike Vadi, Annelore Haems, Lisa Wijns, Inge Bruggeman, Jon Huyghe, Dario Priem, Peter Vandenabeele & Mathieu JM Bertrand

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  1. Tom Delanghe
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Contributions

TD and MJMB designed the study and wrote the manuscript. TD additionally performed the experiments and analyzed results. MV, AH and LW performed experiments to support the conclusions of the story. DP and JH provided feedback that was crucial to develop the project. PV and IB helped in cloning the constructs for the TAB2 NZF deletion.

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Correspondence to Mathieu JM Bertrand.

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Delanghe, T., Vadi, M., Haems, A. et al. TAB2 controls a TAK1-independent cell death checkpoint at the level of TNFR1 complex II in the TNF pathway. Cell Death Differ 33, 64–76 (2026). https://doi.org/10.1038/s41418-025-01568-7

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