A novel role for RIP1 kinase in mediating TNFα production.
Receptor-interacting protein 1 (RIP1) is a Ser/Thr kinase with both kinase-dependent and kinase-independent roles in death receptor signaling. The kinase activity of RIP1 is required for necroptosis, a caspase-independent pathway of programmed cell death. In some cell types, the inhibition of caspases leads to autocrine production of TNFα, which then activates necroptosis. Here, we describe a novel role for RIP1 kinase in regulating TNFα production after caspase inhibition. Caspase inhibitors activate RIP1 kinase and another protein, EDD, to mediate JNK signaling, which stimulates Sp1-dependent transcription of TNFα. This pathway is independent of nuclear factor κB and also occurs after Smac mimetic/IAP antagonist treatment or the loss of TNF receptor-associated factor 2 (Traf2). These findings implicate cIAP1/2 and Traf2 as negative regulators of this RIP1 kinase-dependent TNFα production pathway and suggest a novel role for RIP1 kinase in mediating TNFα production under certain conditions.
Department of Cell Biology, Harvard Medical School, Boston, MA 02115, USA.
D E
DE
Christofferson
Y
Y
Li
J
J
Hitomi
W
W
Zhou
C
C
Upperman
H
H
Zhu
S A
SA
Gerber
S
S
Gygi
J
J
Yuan
D000818:Animals; D017209:Apoptosis; D061945:Caspase Inhibitors / Q000494:pharmacology; D020169:Caspases / Q000378:metabolism; D002460:Cell Line; D020690:GTPase-Activating Proteins / Q000378:metabolism*; D051379:Mice; D015398:Signal Transduction; D047992:TNF Receptor-Associated Factor 2 / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000096:biosynthesis*; D044767:Ubiquitin-Protein Ligases / Q000378:metabolism
D061945:Caspase Inhibitors; D020690:GTPase-Activating Proteins; C490620:Ralbp1 protein, mouse; D047992:TNF Receptor-Associated Factor 2; D014409:Tumor Necrosis Factor-alpha; C489244:UBR5 protein, mouse; D044767:Ubiquitin-Protein Ligases; D020169:Caspases