IAPs limit activation of RIP kinases by TNF receptor 1 during development

Moulin, Maryline; Anderton, Holly; Voss, Anne K.; Thomas, Tim; Wong, Wendy Wei-Lynn; Bankovacki, Aleksandra; Feltham, Rebecca; Chau, Diep; Cook, Wayne D.; Silke, John; Vaux, David L.

doi:10.1038/emboj.2012.18

Cited by 183 publications

(225 citation statements)

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“…4 Most biological studies have focused on cIAP1 rather than cIAP2 because cIAP1 is more highly expressed under normal conditions, suggesting its predominant role. 39 In contrast, the absence of both cIAP1 and cIAP2 is required for complete inhibition of TNFα-mediated survival, suggesting that these inhibitors have redundant functions. 20,21 Evidence also supports that cIAP2 has independent roles from cIAP1 in suppressing apoptosis.…”

Section: Discussionmentioning

confidence: 99%

USP11-dependent selective cIAP2 deubiquitylation and stabilization determine sensitivity to Smac mimetics

Seong

Seo

et al. 2015

Cell Death Differ

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Given their crucial role in apoptosis suppression, inhibitor of apoptosis proteins (IAPs) have recently become attractive targets for cancer therapy. Here, we report that cellular IAP2 (cIAP2) is specifically stabilized in several cancer cell lines, leading to resistance to Smac mimetics, such as BV6 and birinapant. In particular, our results showed that cIAP2 depletion, but not cIAP1 depletion, sensitized cancer cells to Smac mimetic-induced apoptosis. Ubiquitin-specific protease 11 (USP11) is a deubiquitylase that directly stabilizes cIAP2. USP11 overexpression is frequently found in colorectal cancer and melanoma and is correlated with poor survival. In our study, cancer cell lines expressing high levels of USP11 exhibited strong resistance to Smac mimetic-induced cIAP2 degradation. Furthermore, USP11 downregulation sensitized these cells to apoptosis induced by TRAIL and BV6 and suppressed tumor growth in a xenograft model. Finally, the TNFα/JNK pathway induced USP11 expression and maintained cIAP2 stability, suggesting an alternative TNFα-dependent cell survival pathway. Collectively, our data suggest that USP11-stabilized cIAP2 may serve as a barrier against IAP-targeted clinical approaches.

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Section: Discussionmentioning

confidence: 99%

USP11-dependent selective cIAP2 deubiquitylation and stabilization determine sensitivity to Smac mimetics

Seong

Seo

et al. 2015

Cell Death Differ

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“…Likewise, animals that lack the caspase-8 adaptor FADD or FLIP, which resembles caspase-8 but lacks a catalytic site (Wilson et al 2009), also die at E10.5. The Clap1 2/2 Clap2 2/2 double knockout mice are partially rescued to birth (but not beyond) by crossing them to Tnfr1 2/2 mice (Moulin et al 2012), demonstrating that the cIAPs regulate a developmentally important TNF-R1 signaling pathway at E10.5 and suggesting that caspase-8, FADD, and cFLIP are likewise involved in this pathway. Embryonic lethality is also partially rescued by crossing the Xiap 2/2 Clap1 2/2 and Clap1 2/2 Clap2 2/2 mice to Ripk1 2/2 and Ripk3 2/2 mice (Moulin et al 2012), showing that these IAPs function together as critical regulators of an embryonic decision point involving RIP kinase activity.…”

Section: Iaps As Modulators Of Cell Death and Inflammationmentioning

confidence: 96%

“…The Clap1 2/2 Clap2 2/2 double knockout mice are partially rescued to birth (but not beyond) by crossing them to Tnfr1 2/2 mice (Moulin et al 2012), demonstrating that the cIAPs regulate a developmentally important TNF-R1 signaling pathway at E10.5 and suggesting that caspase-8, FADD, and cFLIP are likewise involved in this pathway. Embryonic lethality is also partially rescued by crossing the Xiap 2/2 Clap1 2/2 and Clap1 2/2 Clap2 2/2 mice to Ripk1 2/2 and Ripk3 2/2 mice (Moulin et al 2012), showing that these IAPs function together as critical regulators of an embryonic decision point involving RIP kinase activity. Consistently, recent evidence indicates that XIAP, cIAP1, and cIAP2 together control the assembly of an upstream celldeath-inducing platform dubbed the "Ripoptosome" (also referred to as Complex-II and Necrosome) (Fig.…”

Section: Iaps As Modulators Of Cell Death and Inflammationmentioning

confidence: 96%

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Inhibitor of Apoptosis (IAP) Proteins-Modulators of Cell Death and Inflammation

Silke

Meier

2013

Cold Spring Harbor Perspectives in Biology

267

214

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“…12,13 cIAP1/2 are required for TNF-induced canonical NF-kB activation. 10,[14][15][16] Consequently, their depletion, obtained either genetically or by the use of Smac Mimetics (SM), also induces a switch to apoptosis. Intriguingly, in the absence of cIAP1/2, TNF-induced death was shown to rely on RIPK1 and not on TRADD, 12,15,[17][18][19] suggesting that cIAP1/2 additionally regulate an NF-kB-independent cell death checkpoint in the TNFR1 pathway.…”

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confidence: 99%

RIPK3 contributes to TNFR1-mediated RIPK1 kinase-dependent apoptosis in conditions of cIAP1/2 depletion or TAK1 kinase inhibition

et al. 2013

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Receptor-interacting protein kinase (RIPK) 1 and RIPK3 have emerged as essential kinases mediating a regulated form of necrosis, known as necroptosis, that can be induced by tumor necrosis factor (TNF) signaling. As a consequence, inhibiting RIPK1 kinase activity and repressing RIPK3 expression levels have become commonly used approaches to estimate the contribution of necroptosis to specific phenotypes. Here, we report that RIPK1 kinase activity and RIPK3 also contribute to TNFinduced apoptosis in conditions of cellular inhibitor of apoptosis 1 and 2 (cIAP1/2) depletion or TGF-b-activated kinase 1 (TAK1) kinase inhibition, implying that inhibition of RIPK1 kinase activity or depletion of RIPK3 under cell death conditions is not always a prerequisite to conclude on the involvement of necroptosis. Moreover, we found that, contrary to cIAP1/2 depletion, TAK1 kinase inhibition induces assembly of the cytosolic RIPK1/Fas-associated protein with death domain/caspase-8 apoptotic TNF receptor 1 (TNFR1) complex IIb without affecting the RIPK1 ubiquitylation status at the level of TNFR1 complex I. These results indicate that the recruitment of TAK1 to the ubiquitin (Ub) chains, and not the Ub chains per se, regulates the contribution of RIPK1 to the apoptotic death trigger. In line with this, we found that cylindromatosis repression only provided protection to TNFmediated RIPK1-dependent apoptosis in condition of reduced RIPK1 ubiquitylation obtained by cIAP1/2 depletion but not upon TAK1 kinase inhibition, again arguing for a role of TAK1 in preventing RIPK1-dependent apoptosis downstream of RIPK1 ubiquitylation. Importantly, we found that this function of TAK1 was independent of its known role in canonical nuclear factor-jB (NF-jB) activation. Our study therefore reports a new function of TAK1 in regulating an early NF-jB-independent cell death checkpoint in the TNFR1 apoptotic pathway. In both TNF-induced RIPK1 kinase-dependent apoptotic models, we found that RIPK3 contributes to full caspase-8 activation independently of its kinase activity or intact RHIM domain. In contrast, RIPK3 participates in caspase-8 activation by acting downstream of the cytosolic death complex assembly, possibly via reactive oxygen species generation. Tumor necrosis factor (TNF) is a pleiotropic cytokine that controls a variety of cellular responses, including proliferation, differentiation, inflammatory cytokine production, survival and death. 1 TNF signals by binding and activating two cell surface receptors, TNF receptor (TNFR) 1 and TNFR2, 2 but most of its biological activities have been associated with TNFR1. 3 In most cell types, TNFR1 activation does not induce cell death but instead leads to the transcriptional upregulation of genes encoding pro-survival and pro-inflammatory molecules. 4 This function is mediated by the assembly of a plasma membranebound multiprotein signaling complex, referred to as TNFR1 complex I, 5 that contains TNF receptor-associated death domain (TRADD), receptor-interacting protein kinase 1 (RIPK1, also know...

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IAPs limit activation of RIP kinases by TNF receptor 1 during development

Cited by 183 publications

References 51 publications

USP11-dependent selective cIAP2 deubiquitylation and stabilization determine sensitivity to Smac mimetics

USP11-dependent selective cIAP2 deubiquitylation and stabilization determine sensitivity to Smac mimetics

Inhibitor of Apoptosis (IAP) Proteins-Modulators of Cell Death and Inflammation

RIPK3 contributes to TNFR1-mediated RIPK1 kinase-dependent apoptosis in conditions of cIAP1/2 depletion or TAK1 kinase inhibition

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