5/21/2018 R.hightlight - DR5 Unfolds ER Stress
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Endoplasmic reticulum (ER) stresscaused by the accumulation
of
unfolded proteins in the ER lumenactivates the unfolded
proteinresponse (UPR) to control the
protein-folding capacity of the orga-nelle. When ER stress is
unmitigated,the UPR activates apoptosis through
the interplay of two key mediators,protein kinase Rlike kinase
(PERK)and inositol-requiring enzyme 1
(IRE1); however, the mechanismsregulating apoptosis
initiationwere unclear. Lu et al. now show
that ER-stress-induced apoptosis iscontrolled by death receptor
5 (DR5)and that DR5 levels are regulated
by the opposing activities of PERKand IRE1.
The authors observed that thetreatment of human cell lines
with
various ER stressors, such as the ERcalcium pump inhibitor
thapsigargin,led to apoptosis through the activa-
tion of caspase 8, the initiatorcaspase downstream of the
deathreceptor pathway. Next, the authors
examined which of the death recep-tors activates caspase 8 in
responseto ER stress. They found that several
ER stressors induced DR5 expressionand that these stressors had
muchless impact on other death receptors.
Furthermore, ER stress induced theformation of the caspase
8-activatingcomplex, comprising caspase 8,
DR5 and the caspase 8 adaptor Fas-associated death domain
(FADD).Importantly, activation of DR5
occurred intracellularly and indepen-
dently of its extracellular ligand TNF-related
apoptosis-inducing ligand
(TRAIL; also known as APO2L).Moreover, DR5 depletion
stronglyinhibited both caspase activation and
apoptosis. These results suggest thatDR5 is crucial for caspase
8-mediatedapoptosis in response to ER stress.
The transcription factors C/EBPhomologous protein (CHOP)
andspliced X-box-binding protein 1
(XBP1s) are major effectors of PERKand IRE1, respectively. The
authors
found that ER stressors induced
persistent expression of CHOPand transient expression of
XBP1s.
Depletion of CHOP blocked theupregulation of DR5mRNA by ER
stressors, whereas knockdown of thetranscriptional targets of
CHOP didnot, which indicated that CHOP
controls DR5mRNA accumulationdirectly. By contrast, IRE1
medi-ated DR5mRNA decay, and IRE1
depletion or inhibition accentuatedER-stress-induced DR5
upregulation,caspase 8 activation and apoptosis.
Interestingly, XBP1s depletionaccelerated DR5mRNA decay
anddecreased apoptosis. These results
suggest that IRE1 counteractsPERK-mediated apoptosis by
directlydecreasing DR5transcript levels.
In summary, DR5 integratesopposing UPR signals to
controlER-stress-induced apoptosis:
PERKCHOP activity induces DR5
transcription, whereas IRE1 pro-motes DR5mRNA decay. Thus,
DR5
levels are a measure of the persistenceof ER stress, and are
controlled bythe opposing activities of PERK
and IRE1 to define a time windowfor adaptation to ER stress
beforecommitting cells to apoptosis.
Eytan Zlotorynski
APOPTOSIS
DR5 unfolds ER stress
ORIGINAL RESEARCH PAPERLu, M. et al.
Opposing unfolded-protein-response signals
converge on death receptor 5 to control
apoptosis.Science345, 98101 (2014)
FURTHER READINGHetz, C. The unfolded
protein response: controlling cell fate decisions
under ER stress and beyond. Nature Rev. Mol.Cell Biol. 13, 89102
(2012)
DR5 integrates
opposing
UPR signals
to control
ER-stress-
induced
apoptosis
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R E S E A R C H H I G H L I G H T S
NATURE REVIEWS |MOLECULAR CELL BIOLOGY VOLUME 15 |AUGUST
2014
Nature Reviews Molecular Cell Biology|AOP, published online 16
July 2014; doi:10.1038/nrm3843
2014 Macmillan Publishers Limited. All rights reserved
