PMID- 25882049
OWN - NLM
STAT- MEDLINE
DCOM- 20160509
LR  - 20220408
IS  - 1476-5403 (Electronic)
IS  - 1350-9047 (Print)
IS  - 1350-9047 (Linking)
VI  - 22
IP  - 11
DP  - 2015 Nov
TI  - TRAF2 is a biologically important necroptosis suppressor.
PG  - 1846-57
LID - 10.1038/cdd.2015.35 [doi]
AB  - Tumor necrosis factor alpha (TNFalpha) triggers necroptotic cell death through an 
      intracellular signaling complex containing receptor-interacting protein kinase 
      (RIPK) 1 and RIPK3, called the necrosome. RIPK1 phosphorylates RIPK3, which 
      phosphorylates the pseudokinase mixed lineage kinase-domain-like (MLKL)-driving 
      its oligomerization and membrane-disrupting necroptotic activity. Here, we show 
      that TNF receptor-associated factor 2 (TRAF2)-previously implicated in apoptosis 
      suppression-also inhibits necroptotic signaling by TNFalpha. TRAF2 disruption in 
      mouse fibroblasts augmented TNFalpha-driven necrosome formation and RIPK3-MLKL 
      association, promoting necroptosis. TRAF2 constitutively associated with MLKL, 
      whereas TNFalpha reversed this via cylindromatosis-dependent TRAF2 deubiquitination. 
      Ectopic interaction of TRAF2 and MLKL required the C-terminal portion but not the 
      N-terminal, RING, or CIM region of TRAF2. Induced TRAF2 knockout (KO) in adult 
      mice caused rapid lethality, in conjunction with increased hepatic necrosome 
      assembly. By contrast, TRAF2 KO on a RIPK3 KO background caused delayed 
      mortality, in concert with elevated intestinal caspase-8 protein and activity. 
      Combined injection of TNFR1-Fc, Fas-Fc and DR5-Fc decoys prevented death upon 
      TRAF2 KO. However, Fas-Fc and DR5-Fc were ineffective, whereas TNFR1-Fc and 
      interferon alpha receptor (IFNAR1)-Fc were partially protective against lethality 
      upon combined TRAF2 and RIPK3 KO. These results identify TRAF2 as an important 
      biological suppressor of necroptosis in vitro and in vivo.
FAU - Petersen, S L
AU  - Petersen SL
AD  - Cancer Immunology, Genentech, Inc., 1 DNA Way, South San Francisco, CA 94080, 
      USA.
FAU - Chen, T T
AU  - Chen TT
AD  - Cancer Immunology, Genentech, Inc., 1 DNA Way, South San Francisco, CA 94080, 
      USA.
FAU - Lawrence, D A
AU  - Lawrence DA
AD  - Cancer Immunology, Genentech, Inc., 1 DNA Way, South San Francisco, CA 94080, 
      USA.
FAU - Marsters, S A
AU  - Marsters SA
AD  - Cancer Immunology, Genentech, Inc., 1 DNA Way, South San Francisco, CA 94080, 
      USA.
FAU - Gonzalvez, F
AU  - Gonzalvez F
AD  - Cancer Immunology, Genentech, Inc., 1 DNA Way, South San Francisco, CA 94080, 
      USA.
FAU - Ashkenazi, A
AU  - Ashkenazi A
AD  - Cancer Immunology, Genentech, Inc., 1 DNA Way, South San Francisco, CA 94080, 
      USA.
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20150417
PL  - England
TA  - Cell Death Differ
JT  - Cell death and differentiation
JID - 9437445
RN  - 0 (TNF Receptor-Associated Factor 2)
RN  - EC 2.7.- (MLKL protein, mouse)
RN  - EC 2.7.- (Protein Kinases)
RN  - EC 2.7.11.1 (Receptor-Interacting Protein Serine-Threonine Kinases)
RN  - EC 2.7.11.1 (Ripk1 protein, mouse)
RN  - EC 2.7.11.1 (Ripk3 protein, mouse)
SB  - IM
MH  - Animals
MH  - Apoptosis/genetics/physiology
MH  - Cell Death/genetics/physiology
MH  - Fibroblasts/metabolism
MH  - Immunohistochemistry
MH  - Mice
MH  - Mice, Knockout
MH  - Protein Binding
MH  - Protein Kinases/genetics/metabolism
MH  - Receptor-Interacting Protein Serine-Threonine Kinases/genetics/metabolism
MH  - TNF Receptor-Associated Factor 2/genetics/*metabolism
MH  - Ubiquitination/genetics/physiology
PMC - PMC4648330
EDAT- 2015/04/18 06:00
MHDA- 2016/05/10 06:00
PMCR- 2016/11/01
CRDT- 2015/04/18 06:00
PHST- 2014/11/11 00:00 [received]
PHST- 2015/02/11 00:00 [revised]
PHST- 2015/02/24 00:00 [accepted]
PHST- 2015/04/18 06:00 [entrez]
PHST- 2015/04/18 06:00 [pubmed]
PHST- 2016/05/10 06:00 [medline]
PHST- 2016/11/01 00:00 [pmc-release]
AID - cdd201535 [pii]
AID - 10.1038/cdd.2015.35 [doi]
PST - ppublish
SO  - Cell Death Differ. 2015 Nov;22(11):1846-57. doi: 10.1038/cdd.2015.35. Epub 2015 
      Apr 17.