Stress-induced decrease in TRAF2 stability is mediated by Siah2.
TRAF2 serves as a central regulator of the cellular response to stress and cytokines through the regulation of key stress-signaling cascades. Here we demonstrate that wild-type, but not RING mutant, Siah2 targets TRAF2 for ubiquitylation and degradation in vitro. Siah2 mediates equally efficient ubiquitylation of RING mutant TRAF2. In vivo, Siah2 primarily targets TRAF2 for degradation under stress conditions. Tumor necrosis factor-alpha (TNF-alpha) and actinomycin D treatment results in accelerated TRAF2 degradation in wild-type mouse embryo fibroblasts (MEFs), as compared with Siah2(-/-) cells. Similarly, TRAF2 half-life is prolonged in Siah2(-/-) compared with wild-type MEFs subjected to stress stimuli. Siah2 efficiently decreases TNF-alpha-dependent induction of JNK activity and transcriptional activation of NF-kappaB. Apoptosis induced by TNF-alpha and actinomycin D treatment is increased upon expression of Siah2, or attenuated upon expression of TRAF2 or RING mutant Siah2. Identifying Siah2 as a regulator of TRAF2 stability reveals its role in the regulation of TRAF2 signaling following exposure to stress.
Habelhah
Hasem
H
Ruttenberg Cancer Center and Department of Biochemistry and Molecular Biology, Mount Sinai School of Medicine, New York, NY 10029, USA.
Frew
Ian J
IJ
Laine
Aaron
A
Janes
Peter W
PW
Relaix
Frederic
F
Sassoon
David
D
Bowtell
David D L
DD
Ronai
Ze'ev
Z
D000818:Animals; D051379:Mice; D018345:Mice, Knockout; D016328:NF-kappa B / Q000378:metabolism; D009687:Nuclear Proteins / Q000502:physiology*; D018384:Oxidative Stress; D011506:Proteins / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction; D047992:TNF Receptor-Associated Factor 2; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology; D025801:Ubiquitin / Q000378:metabolism; D044767:Ubiquitin-Protein Ligases; D014466:Ultraviolet Rays; D000098563:Seven in Absentia Proteins
D016328:NF-kappa B; D009687:Nuclear Proteins; D011506:Proteins; D047992:TNF Receptor-Associated Factor 2; D014409:Tumor Necrosis Factor-alpha; D025801:Ubiquitin; D044767:Ubiquitin-Protein Ligases; D000098563:Seven in Absentia Proteins