Death receptor 3 mediates necroptotic cell death.
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.
Institute of Clinical Microbiology and Hygiene, University Hospital Regensburg, Franz-Josef-Strauss-Allee 11, 93053, Regensburg, Germany.
Sebastian
S
Bittner
Institute of Clinical Microbiology and Hygiene, University Hospital Regensburg, Franz-Josef-Strauss-Allee 11, 93053, Regensburg, Germany.
Gertrud
G
Knoll
Institute of Clinical Microbiology and Hygiene, University Hospital Regensburg, Franz-Josef-Strauss-Allee 11, 93053, Regensburg, Germany. martin.ehrenschwender@ukr.de.
Martin
0000-0003-4681-8628
M
Ehrenschwender
D000818:Animals; D020169:Caspases / Q000378:metabolism; D002460:Cell Line; D018841:HSP90 Heat-Shock Proteins / Q000378:metabolism; D006801:Humans; D020930:MAP Kinase Kinase Kinases / Q000378:metabolism; D051379:Mice; D009336:Necrosis; D028861:Nuclear Pore Complex Proteins / Q000378:metabolism; D016601:RNA-Binding Proteins / Q000378:metabolism; D017382:Reactive Oxygen Species / Q000378:metabolism; D053422:Receptor-Interacting Protein Serine-Threonine Kinases / Q000378:metabolism; D053219:Receptors, Tumor Necrosis Factor, Member 25 / Q000378:metabolism*; D053380:Tumor Necrosis Factor Ligand Superfamily Member 15 / Q000378:metabolism; D000099151:MAP Kinase Kinase Kinase 7
D020169:Caspases; D018841:HSP90 Heat-Shock Proteins; D020930:MAP Kinase Kinase Kinases; D028861:Nuclear Pore Complex Proteins; D016601:RNA-Binding Proteins; D017382:Reactive Oxygen Species; D053422:Receptor-Interacting Protein Serine-Threonine Kinases; D053219:Receptors, Tumor Necrosis Factor, Member 25; D053380:Tumor Necrosis Factor Ligand Superfamily Member 15; D000099151:MAP Kinase Kinase Kinase 7; C119724:AGFG1 protein, human; C506033:TNFRSF25 protein, human; C117026:TNFSF15 protein, human; C119705:RIPK3 protein, human
Death receptor 3; MLKL; Necroptosis; RIP3; TL1A; TNFRSF25