RIPK1 is not essential for TNFR1-induced activation of NF-kappaB.
On TNF binding, receptor-interacting protein kinase 1 (RIPK1) is recruited to the cytoplasmic domain of TNFR1, at which it becomes ubiquitylated and serves as a platform for recruitment and activation of NEMO/IKK1/IKK2 and TAK1/TAB2. RIPK1 is commonly thought to be required for the activation of canonical NF-kappaB and for inhibition TNFR1-induced apoptosis. RIPK1 has, however, also been reported to be essential for TNFR1-induced apoptosis when cIAPs are depleted. To determine the role of RIPK1 in TNF/IAP antagonist-induced death, we compared wild type (WT) and RIPK1(-/-) mouse embryonic fibroblasts (MEFs) treated with these compounds. On being treated with TNF plus IAP antagonist, RIPK1(-/-) MEFs survived, unlike WT MEFs, demonstrating a killing activity of RIPK1. Surprisingly, however, on being treated with TNF alone, RIPK1(-/-) MEFs activated canonical NF-kappaB and did not die. Furthermore, several cell types from E18 RIPK1(-/-) embryos seem to activate NF-kappaB in response to TNF. These data indicate that models proposing that RIPK1 is essential for TNFR1 to activate canonical NF-kappaB are incorrect.
Wong
W W-L
WW
Department of Biochemistry, La Trobe University, Kingsbury Drive, Melbourne, Victoria 3086, Australia.
Gentle
I E
IE
Nachbur
U
U
Anderton
H
H
Vaux
D L
DL
Silke
J
J
D000818:Animals; D002478:Cells, Cultured; D005347:Fibroblasts / Q000166:cytology / Q000502:physiology; D051379:Mice; D018345:Mice, Knockout; D016328:NF-kappa B / Q000235:genetics / Q000378:metabolism*; D053422:Receptor-Interacting Protein Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism*; D047888:Receptors, Tumor Necrosis Factor, Type I / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction / Q000502:physiology
D016328:NF-kappa B; D047888:Receptors, Tumor Necrosis Factor, Type I; D053422:Receptor-Interacting Protein Serine-Threonine Kinases