The endogenous caspase-8 inhibitor c-FLIPL regulates ER morphology and crosstalk
with mitochondria
#MMPMID25501600
Marini ES
; Giampietri C
; Petrungaro S
; Conti S
; Filippini A
; Scorrano L
; Ziparo E
Cell Death Differ
2015[Jul]; 22
(7
): 1131-43
PMID25501600
show ga
Components of the death receptor-mediated pathways like caspase-8 have been
identified in complexes at intracellular membranes to spatially restrict the
processing of local targets. In this study, we report that the long isoform of
the cellular FLICE-inhibitory protein (c-FLIP(L)), a well-known inhibitor of the
extrinsic cell death initiator caspase-8, localizes at the endoplasmic reticulum
(ER) and mitochondria-associated membranes (MAMs). ER morphology was disrupted
and ER Ca(2+)-release as well as ER-mitochondria tethering was decreased in
c-FLIP(-/-) mouse embryonic fibroblasts (MEFs). Mechanistically, c-FLIP ablation
resulted in enhanced basal caspase-8 activation and in caspase-mediated
processing of the ER-shaping protein reticulon-4 (RTN4) that was corrected by
re-introduction of c-FLIP(L) and caspase inhibition, resulting in the recovery of
a normal ER morphology and ER-mitochondria juxtaposition. Thus, the caspase-8
inhibitor c-FLIP(L) emerges as a component of the MAMs signaling platforms, where
caspases appear to regulate ER morphology and ER-mitochondria crosstalk by
impinging on ER-shaping proteins like the RTN4.
|*Signal Transduction
[MESH]
|Animals
[MESH]
|CASP8 and FADD-Like Apoptosis Regulating Protein/*metabolism
[MESH]
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