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Death receptor 3 mediates necroptotic cell death

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Abstract

Death receptor 3 (DR3) was initially identified as a T cell co-stimulatory and pro-inflammatory molecule, but further studies revealed a more complex role of DR3 and its ligand TL1A. Although being a death receptor, DR3 gained to date predominantly attention as a contributor to inflammation-driven diseases. In our study, we investigated the cell death pathways associated with DR3. We show that in addition to apoptosis, DR3 can robustly trigger necroptotic cell death and provide evidence for TL1A-induced, DR3-mediated necrosome assembly. DR3-mediated necroptosis critically depends on receptor-interacting protein 1 (RIP1) and RIP3, the core components of the necroptotic machinery, which activate the pseudo-kinase mixed lineage kinase domain-like, the prototypic downstream effector molecule of necroptosis. Moreover, we demonstrate that DR3-mediated necroptotic cell death is accompanied by, but does not depend on generation of reactive oxygen species. In sum, we identify DR3 as a novel necroptosis-inducing death receptor and thereby lay ground for elucidating the (patho-) physiological relevance of DR3-mediated necroptotic cell death in vitro and in vivo.

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Acknowledgments

ME is supported by grants from Deutsche Forschungsgemeinschaft (DFG Grant EH 465/2-1), the Roggenbuck Stiftung and the Medical Faculty of the University of Regensburg (“ReForM-B”).

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  1. Institute of Clinical Microbiology and Hygiene, University Hospital Regensburg, Franz-Josef-Strauss-Allee 11, 93053, Regensburg, Germany

    Sebastian Bittner, Gertrud Knoll & Martin Ehrenschwender

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Correspondence to Martin Ehrenschwender.

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Bittner, S., Knoll, G. & Ehrenschwender, M. Death receptor 3 mediates necroptotic cell death. Cell. Mol. Life Sci. 74, 543–554 (2017). https://doi.org/10.1007/s00018-016-2355-2

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