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Noncanonical cell death program independent of caspase activation cascade and
necroptotic modules is elicited by loss of TGF?-activated kinase 1
#MMPMID28592892
Mihaly SR
; Sakamachi Y
; Ninomiya-Tsuji J
; Morioka S
Sci Rep
2017[Jun]; 7
(1
): 2918
PMID28592892
show ga
Programmed cell death (PCD) occurs in several forms including apoptosis and
necroptosis. Apoptosis is executed by the activation of caspases, while
necroptosis is dependent on the receptor interacting protein kinase 3 (RIPK3).
Precise control of cell death is crucial for tissue homeostasis. Indeed,
necroptosis is triggered by caspase inhibition to ensure cell death. Here we
identified a previously uncharacterized cell death pathway regulated by TAK1,
which is unexpectedly provoked by inhibition of caspase activity and necroptosis
cascades. Ablation of TAK1 triggers spontaneous death in macrophages.
Simultaneous inhibition of caspases and RIPK3 did not completely restore cell
viability. Previous studies demonstrated that loss of TAK1 in fibroblasts causes
TNF-induced apoptosis and that additional inhibition of caspase leads to
necroptotic cell death. However, we surprisingly found that caspase and RIPK3
inhibitions do not completely suppress cell death in Tak1-deficient cells.
Mechanistically, the execution of the third cell death pathway in Tak1-deficient
macrophages and fibroblasts were mediated by RIPK1-dependent rapid accumulation
of reactive oxygen species (ROS). Conversely, activation of RIPK1 was sufficient
to induce cell death. Therefore, loss of TAK1 elicits noncanonical cell death
which is mediated by RIPK1-induced oxidative stress upon caspase and necroptosis
inhibition to further ensure induction of cell death.
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