c-IAP1 and UbcH5 promote K11-linked polyubiquitination of RIP1 in TNF signalling

Dynek, Jasmin N.; Goncharov, Tatiana; Dueber, Erin C.; Fedorova, Anna; Izrael-Tomasevic, Anita; Phu, Lilian; Helgason, Elizabeth; Fairbrother, Wayne J.; Deshayes, Kurt; Kirkpatrick, Donald S.; Vucic, Domagoj

doi:10.1038/emboj.2010.300

Cited by 311 publications

(272 citation statements)

References 45 publications

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“…Although Cezanne was reported to inhibit NF-κB signaling through removing K63-linked polyubiquitin chains from RIP1 [24,25], Bremm et al [40] found that Cezanne preferentially hydrolyzes K11-linked polyubiquitin chains. Interestingly, a recent study reported that K11-linked polyubiquitin chains of RIP1 can also serve as a platform for recruitment of NEMO and participate in TNF-α-stimulated NF-κB activation [41]. In this respect, investigating the selectivity of Cezanne for K11-or K63-linked ubiquitin chains may reveal a novel regulatory mechanism of NF-κB signaling and facilitate the discovery of new therapeutic targets for cancer treatment and prevention.…”

Section: Discussionmentioning

confidence: 99%

miR-486 sustains NF-κB activity by disrupting multiple NF-κB-negative feedback loops

Song

Lin²,

Gong³

et al. 2012

Cell Res

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Deubiquitinases, such as CYLD, A20 and Cezanne, have emerged as important negative regulators that balance the strength and the duration of NF-κB signaling through feedback mechanisms. However, how these serial feedback loops are simultaneously disrupted in cancers, which commonly exhibit constitutively activated NF-κB, remains puzzling. Herein, we report that miR-486 directly suppresses NF-κB-negative regulators, CYLD and Cezanne, as well as multiple A20 activity regulators, including ITCH, TNIP-1, TNIP-2 and TNIP-3, resulting in promotion of ubiquitin conjugations in NF-κB signaling and sustained NF-κB activity. Furthermore, we demonstrate that upregulation of miR-486 promotes glioma aggressiveness both in vitro and in vivo through activation of NF-κB signaling pathway. Importantly, miR-486 levels in primary gliomas significantly correlate with NF-κB activation status. These findings uncover a novel mechanism for constitutive NF-κB activation in gliomas and support a functionally and clinically relevant epigenetic mechanism in cancer progression.

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Section: Discussionmentioning

confidence: 99%

miR-486 sustains NF-κB activity by disrupting multiple NF-κB-negative feedback loops

Song

Lin²,

Gong³

et al. 2012

Cell Res

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confidence: 99%

“…6 Within this complex, RIPK1 and other proteins are rapidly conjugated with Ub chains of various types. [7][8][9][10] These Ub chains act as scaffolds for the recruitment and activation of the TAK1-binding protein 2/3 (TAB2/3)-TGF-bactivated kinase 1 (TAK1) complex and the inhibitor of nuclear factor-kB (NF-kB) kinase (IKK) complex (NEMO-IKKa-IKKb), which subsequently leads to the activation of the mitogenactivated protein kinases and canonical NF-kB signaling pathways that collectively drive transcription of genes that prevent cell death and sustain inflammation. Accordingly, when the NF-kB response is inhibited, either genetically or by the use of the general translation inhibitor cycloheximide (CHX), TNFR1 ligation switches from a pro-survival to a pro-apoptotic response.…”

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confidence: 99%

“…11 The molecular mechanism accounting for the differential assembly of complex IIa versus IIb is poorly understood, but suggested to rely on RIPK1 ubiquitylation status in complex I. Indeed, cIAP1/2 act as direct ubiquitin ligases for RIPK1 8,14,15,20,21 and cIAP1/2-mediated RIPK1 ubiquitylation in complex I is believed to prevent the transition of RIPK1 from complex I to complex II. 12,15,22,23 A notion supported by the fact that repression of the RIPK1 deubiquitinase cylindromatosis (CYLD) inhibits recruitment of RIPK1 to complex IIb.…”

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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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“…[5][6][7][8][9] c-IAP1/2 and LUBAC target RIP1 for K11, K63 and linear polyubiquitination priming RIP1 for the recruitment of two kinase-containing complexes, namely, TAK1/TAK1-binding protein 1 (TAB1)/TAB2 and NEMO/ inhibitor of NF-κB kinase α (IKKα)/IKKβ. 5,[10][11][12][13] Ultimately, activation of IKKβ leads to the phosphorylation and proteasomal degradation of IκBα and the nuclear translocation of NF-κB, a pathway defined as the classical, or the canonical, NF-κB pathway. [14][15][16] Besides its role in the activation of NF-κB, the dissociation of complex I from TNFR1 triggers the recruitment of Fas-associated protein with death domain (FADD) and caspase-8 to form a cytosolic death complex, initially defined as complex II.…”

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confidence: 99%

NIK promotes tissue destruction independently of the alternative NF-κB pathway through TNFR1/RIP1-induced apoptosis

et al. 2015

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NF-κB-inducing kinase (NIK) is well-known for its role in promoting p100/NF-κB2 processing into p52, a process defined as the alternative, or non-canonical, NF-κB pathway. Here we reveal an unexpected new role of NIK in TNFR1-mediated RIP1-dependent apoptosis, a consequence of TNFR1 activation observed in c-IAP1/2-depleted conditions. We show that NIK stabilization, obtained by activation of the non-death TNFRs Fn14 or LTβR, is required for TNFα-mediated apoptosis. These apoptotic stimuli trigger the depletion of c-IAP1/2, the phosphorylation of RIP1 and the RIP1 kinase-dependent assembly of the RIP1/FADD/caspase-8 complex.In the absence of NIK, the phosphorylation of RIP1 and the formation of RIP1/FADD/caspase-8 complex are compromised while c-IAP1/2 depletion is unaffected. In vitro kinase assays revealed that recombinant RIP1 is a bona fide substrate of NIK. In vivo, we demonstrated the requirement of NIK pro-death function, but not the processing of its substrate p100 into p52, in a mouse model of TNFR1/LTβR-induced thymus involution. In addition, we also highlight a role for NIK in hepatocyte apoptosis in a mouse model of virus-induced TNFR1/RIP1-dependent liver damage. We conclude that NIK not only contributes to lymphoid organogenesis, inflammation and cell survival but also to TNFR1/RIP1-dependent cell death independently of the alternative NF-κB pathway.

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c-IAP1 and UbcH5 promote K11-linked polyubiquitination of RIP1 in TNF signalling

Cited by 311 publications

References 45 publications

miR-486 sustains NF-κB activity by disrupting multiple NF-κB-negative feedback loops

miR-486 sustains NF-κB activity by disrupting multiple NF-κB-negative feedback loops

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

NIK promotes tissue destruction independently of the alternative NF-κB pathway through TNFR1/RIP1-induced apoptosis

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