Noncanonical cell death program independent of caspase activation cascade and necroptotic modules is elicited by loss of TGFβ-activated kinase 1

Abstract

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.

Synthetic lethality between VPS 4A and VPS 4B triggers an inflammatory response in colorectal cancer

“…However, HCT116 cells possess RIPK1 (Moriwaki et al , ). A recent report indicates RIPK1 can mediate noncanonical caspase‐ and RIPK3‐independent cell death (Mihaly et al , ). Indeed, inhibition of RIPK1 activity by necrostatin‐1 improved the viability of VPS4A+B‐depleted cells, although only to a limited degree similar to the effect of caspase inhibition by Q‐VD‐Oph (Fig D).…”

TAK1 restricts spontaneous NLRP3 activation and cell death to control myeloid proliferation

“…Although TAK1 prosurvival function in different cell types is well established, there are conflicting studies regarding the mechanism and nature of cell death observed in TAK1 KO cells. In some studies, both RIPK1 and RIPK3 have been shown to promote necrotic and apoptotic cell death in TAK1-deficient cells ( Vanlangenakker et al, 2011 ; Guo et al, 2016 ); however, other studies report that RIPK1, RIPK3 or both are dispensable for the cell death observed in TAK1 KO cells ( Morioka et al, 2014 ; Dondelinger et al, 2015 ; Mihaly et al, 2017 ). Overall, the molecular mechanisms responsible for hyperactivation of the inflammatory immune response seen in conditions of TAK1 inactivation remain poorly understood.…”

C-terminal binding protein‑2 mediates cisplatin chemoresistance in esophageal cancer cells via the inhibition of apoptosis

“…Mechanisms underlying the effect of CtBP2 on DDP chemoresistance. Caspase serves essential roles in cell apoptosis, which is a cellular event considered as programmed cell death (31,32). Caspase-3 is one of the crucial downstream effectors of apoptosis (33).…”