PMID- 25299769
OWN - NLM
STAT- MEDLINE
DCOM- 20150707
LR  - 20211021
IS  - 2041-4889 (Electronic)
VI  - 5
IP  - 10
DP  - 2014 Oct 9
TI  - TRAF2 inhibits TRAIL- and CD95L-induced apoptosis and necroptosis.
PG  - e1444
LID - 10.1038/cddis.2014.404 [doi]
AB  - The relevance of the adaptor protein TNF receptor-associated factor 2 (TRAF2) for 
      signal transduction of the death receptor tumour necrosis factor receptor1 
      (TNFR1) is well-established. The role of TRAF2 for signalling by CD95 and the 
      TNF-related apoptosis inducing ligand (TRAIL) DRs, however, is only poorly 
      understood. Here, we observed that knockdown (KD) of TRAF2 sensitised 
      keratinocytes for TRAIL- and CD95L-induced apoptosis. Interestingly, while cell 
      death was fully blocked by the pan-caspase inhibitor 
      benzyloxycarbonyl-Val-Ala-Asp(OMe)-fluoromethylketone (zVAD-fmk) in control 
      cells, TRAF2-depleted keratinocytes were only partly rescued from TRAIL- and 
      CD95L-induced cell death. In line with the idea the only partially protective 
      effect of zVAD-fmk on TRAIL- and CD95L-treated TRAF2-depleted keratinocytes is 
      due to the induction of necroptosis, combined treatment with zVAD-fmk and the 
      receptor interacting protein 1 (RIP1) inhibitor necrostatin-1 [corrected] fully 
      rescued these cells. To better understand the impact of TRAF2 levels on RIP1- and 
      RIP3-dependent necroptosis and RIP3-independent apoptosis, we performed 
      experiments in HeLa cells that lack endogenous RIP3 and HeLa cells stably 
      transfected with RIP3. HeLa cells, in which necroptosis has no role, were 
      markedly sensitised to TRAIL-induced caspase-dependent apoptosis by TRAF2 KD. In 
      RIP3-expressing HeLa transfectants, however, KD of TRAF2 also strongly sensitised 
      for TRAIL-induced necroptosis. Noteworthy, priming of keratinocytes with soluble 
      TWEAK, which depletes the cytosolic pool of TRAF2-containing protein complexes, 
      resulted in strong sensitisation for TRAIL-induced necroptosis but had only a 
      very limited effect on TRAIL-induced apoptosis. The necroptotic TRAIL response 
      was not dependent on endogenously produced TNF and TNFR signalling, since 
      blocking TNF by TNFR2-Fc or anti-TNFalpha had no effect on necroptosis induction. 
      Taken together, we identified TRAF2 not only as a negative regulator of 
      DR-induced apoptosis but in particular also as an antagonist of TRAIL- and 
      CD95L-induced necroptosis.
FAU - Karl, I
AU  - Karl I
AD  - Department of Dermatology, Venereology and Allergology, University Hospital 
      Wurzburg, Wurzburg, Germany.
FAU - Jossberger-Werner, M
AU  - Jossberger-Werner M
AD  - Department of Dermatology, Venereology and Allergology, University Hospital 
      Wurzburg, Wurzburg, Germany.
FAU - Schmidt, N
AU  - Schmidt N
AD  - Department of Dermatology, Venereology and Allergology, University Hospital 
      Wurzburg, Wurzburg, Germany.
FAU - Horn, S
AU  - Horn S
AD  - Department of Dermatology, Venereology and Allergology, University Medical Center 
      Mannheim, University of Heidelberg, Mannheim, Germany.
FAU - Goebeler, M
AU  - Goebeler M
AD  - Department of Dermatology, Venereology and Allergology, University Hospital 
      Wurzburg, Wurzburg, Germany.
FAU - Leverkus, M
AU  - Leverkus M
AD  - Department of Dermatology, Venereology and Allergology, University Medical Center 
      Mannheim, University of Heidelberg, Mannheim, Germany.
FAU - Wajant, H
AU  - Wajant H
AD  - Division of Molecular Internal Medicine, Department of Internal Medicine II, 
      University Hospital Wurzburg, Wurzburg, Germany.
FAU - Giner, T
AU  - Giner T
AD  - Department of Dermatology, Venereology and Allergology, University Hospital 
      Wurzburg, Wurzburg, Germany.
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20141009
PL  - England
TA  - Cell Death Dis
JT  - Cell death & disease
JID - 101524092
RN  - 0 (AGFG1 protein, human)
RN  - 0 (Fas Ligand Protein)
RN  - 0 (Nuclear Pore Complex Proteins)
RN  - 0 (RNA-Binding Proteins)
RN  - 0 (TNF Receptor-Associated Factor 2)
RN  - 0 (TNF-Related Apoptosis-Inducing Ligand)
RN  - 0 (Tumor Necrosis Factor-alpha)
RN  - EC 2.7.11.1 (RIPK3 protein, human)
RN  - EC 2.7.11.1 (Receptor-Interacting Protein Serine-Threonine Kinases)
SB  - IM
EIN - Cell Death Dis. 2014;5:e1556
MH  - *Apoptosis
MH  - Fas Ligand Protein/genetics/*metabolism
MH  - Humans
MH  - Keratinocytes/*cytology/metabolism
MH  - Necrosis
MH  - Nuclear Pore Complex Proteins/genetics/metabolism
MH  - RNA-Binding Proteins/genetics/metabolism
MH  - Receptor-Interacting Protein Serine-Threonine Kinases/genetics/metabolism
MH  - Signal Transduction
MH  - TNF Receptor-Associated Factor 2/genetics/*metabolism
MH  - TNF-Related Apoptosis-Inducing Ligand/genetics/*metabolism
MH  - Tumor Necrosis Factor-alpha/metabolism
PMC - PMC4649511
EDAT- 2014/10/10 06:00
MHDA- 2015/07/08 06:00
PMCR- 2014/10/01
CRDT- 2014/10/10 06:00
PHST- 2014/05/14 00:00 [received]
PHST- 2014/08/08 00:00 [revised]
PHST- 2014/08/26 00:00 [accepted]
PHST- 2014/10/10 06:00 [entrez]
PHST- 2014/10/10 06:00 [pubmed]
PHST- 2015/07/08 06:00 [medline]
PHST- 2014/10/01 00:00 [pmc-release]
AID - cddis2014404 [pii]
AID - 10.1038/cddis.2014.404 [doi]
PST - epublish
SO  - Cell Death Dis. 2014 Oct 9;5(10):e1444. doi: 10.1038/cddis.2014.404.