TAK1 regulates caspase 8 activation and necroptotic signaling via multiple cell death checkpoints.

Xiaoyun Guo,Haifeng Yin,Yi Chen,Jing Li,Qinghang Liu,Lei Li

doi:10.1038/cddis.2016.294

Xiaoyun Guo, Haifeng Yin + Show 4 more

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https://doi.org/10.1038/cddis.2016.294

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Abstract

Necroptosis has emerged as a new form of programmed cell death implicated in a number of pathological conditions such as ischemic injury, neurodegenerative disease, and viral infection. Recent studies indicate that TGFβ-activated kinase 1 (TAK1) is nodal regulator of necroptotic cell death, although the underlying molecular regulatory mechanisms are not well defined. Here we reported that TAK1 regulates necroptotic signaling as well as caspase 8-mediated apoptotic signaling through both NFκB-dependent and -independent mechanisms. Inhibition of TAK1 promoted TNFα-induced cell death through the induction of RIP1 phosphorylation/activation and necrosome formation. Further, inhibition of TAK1 triggered two caspase 8 activation pathways through the induction of RIP1-FADD-caspase 8 complex as well as FLIP cleavage/degradation. Mechanistically, our data uncovered an essential role for the adaptor protein TNF receptor-associated protein with death domain (TRADD) in caspase 8 activation and necrosome formation triggered by TAK1 inhibition. Moreover, ablation of the deubiqutinase CYLD prevented both apoptotic and necroptotic signaling induced by TAK1 inhibition. Finally, blocking the ubiquitin-proteasome pathway prevented the degradation of key pro-survival signaling proteins and necrosome formation. Thus, we identified new regulatory mechanisms underlying the critical role of TAK1 in cell survival through regulation of multiple cell death checkpoints. Targeting key components of the necroptotic pathway (e.g., TRADD and CYLD) and the ubiquitin-proteasome pathway may represent novel therapeutic strategies for pathological conditions driven by necroptosis.

Highlights

Apoptosis and necrosis are two morphologically and mechanistically distinct forms of cell death
Glyceraldehyde 3-phosphate dehydrogenase (GAPDH), a cytoplasmic protein, was more readily detectable from the supernatant compared with High mobility group box 1 (HMGB1), indicating that the release of glyceraldehyde 3-phosphate dehydrogenase (GAPDH) may serve as a new biomarker for plasma membrane disruption/leakage (Figure 1a)
Our results demonstrated that TGFβ-activated kinase 1 (TAK1) functions as a nodal regulator of the tumor necrosis factor receptor 1 (TNFR1)-mediated cell survival/death signaling through regulation of multiple cell death checkpoints

Summary

Introduction

Apoptosis and necrosis are two morphologically and mechanistically distinct forms of cell death. Apoptosis is induced by death receptor- or mitochondria-mediated pathways, showing distinct morphological features including membrane blebing, cell shrinkage, nuclear fragmentation, and chromatin condensation.[1] Recent studies indicate that certain forms of necrosis occur in a highly regulated, programmed fashion. Complex to the complex I leads to the activation of NFκB, which drives the transcription of pro-survival genes Under certain conditions such as inhibition of NFκB signaling or protein synthesis, the TNFR1 complex internalizes and converts to a cell death-inducing complex, termed complex II, with additional recruitment of Fas-associated protein with death domain (FADD) and caspase 8.8–10 TNFR1 signaling can induce the formation of another cell death-inducing complex, known as necrosome, consisting of RIP1, RIP3, and FADD.[11]. TRAF2 and cIAP1/2 act as ubiquitin ligases for RIP1, and lysine 63-linked ubiquitination of RIP1 on lysine 377 is believed to prevent the formation of complex II by stabilizing complex I.17,18 On the other hand, the deubiquitinating enzyme cylindromatosis (CYLD) promotes necroptotic signaling by augmenting RIP1–RIP3 interaction.[19]

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