NEMO Inhibits Programmed Necrosis in an NFκB-Independent Manner by Restraining RIP1

O’Donnell, Marie Anne; Häse, H.; Legarda, Diana; Ting, Adrian T.

doi:10.1371/journal.pone.0041238

Cited by 57 publications

(56 citation statements)

References 67 publications

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“…In contrast to the general notion that NEMO exerts its effects via NF-B, these findings indicate that TAK1 and NEMO can prevent cell death independent of NF-B, at least of the p65 subunit and its main activator in the canonical pathway, IKK2. Previous work has already shown in vitro that TAK1 and NEMO can prevent TNF-induced cell death without the need for NF-B-mediated gene transcription (O'Donnell et al, 2012;Dondelinger et al, 2013). Our study now provides the first in vivo evidence for this novel function of TAK1 and NEMO in brain endothelial cells.…”

Section: Mechanisms Of Brain Endothelial Cell Death Upon Disruption Osupporting

confidence: 65%

Brain endothelial TAK1 and NEMO safeguard the neurovascular unit

Ridder¹,

Wenzel²,

Müller³

et al. 2015

J Cell Biol

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Section: Mechanisms Of Brain Endothelial Cell Death Upon Disruption Osupporting

confidence: 65%

Brain endothelial TAK1 and NEMO safeguard the neurovascular unit

Ridder¹,

Wenzel²,

Müller³

et al. 2015

J Cell Biol

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“…As previously described, NEMO-deficient Jurkat cells were sensitive to TNFinduced cell death, with both a caspase-dependent and independent component ( Fig. 2A) (21,23). Reconstitution of these cells with wild-type NEMO reduced cell death, with the residual cell death being almost completely caspase-dependent, whereas loss of function NEMO mutations affecting the first coiled-coil domain (L153R), the C-terminal zinc finger (C417R), or the UBAN domain (E319AE320A) all failed to prevent cell death in response to TNF (Fig.…”

supporting

confidence: 54%

Recruitment of A20 by the C-terminal domain of NEMO suppresses NF-κB activation and autoinflammatory disease

Zilberman‐Rudenko

Shawver

Wessel

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

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Receptor-induced NF-κB activation is controlled by NEMO, the NF-κB essential modulator. Hypomorphic NEMO mutations result in X-linked ectodermal dysplasia with anhidrosis and immunodeficiency, also referred to as NEMO syndrome. Here we describe a distinct group of patients with NEMO C-terminal deletion (ΔCT-NEMO) mutations. Individuals harboring these mutations develop inflammatory skin and intestinal disease in addition to ectodermal dysplasia with anhidrosis and immunodeficiency. Both primary cells from these patients, as well as reconstituted cell lines with this deletion, exhibited increased IκB kinase (IKK) activity and production of proinflammatory cytokines. Unlike previously described loss-of-function mutations, ΔCT-NEMO mutants promoted increased NF-κB activation in response to TNF and Toll-like receptor stimulation. Investigation of the underlying mechanisms revealed impaired interactions with A20, a negative regulator of NF-κB activation, leading to prolonged accumulation of K63-ubiquitinated RIP within the TNFR1 signaling complex. Recruitment of A20 to the C-terminal domain of NEMO represents a novel mechanism limiting NF-κB activation by NEMO, and its absence results in autoinflammatory disease.ctivation of the NF-κB family of transcription factors is required for normal development, innate and adaptive immunity, and the inflammatory response (1, 2). NF-κB-induced transcription of proinflammatory cytokines and chemokines amplifies immune-response programs and stimulates recruitment of inflammatory cells. Transcriptional activity of the classic NF-κB p65/p50 complex is regulated by the inhibitor of NF-κB kinase (IKK), consisting of the α-and β-catalytic subunits and the NEMO (NF-κB essential modulator, IKKγ) regulatory subunit. IKK activity leads to phosphorylation and K48-linked polyubiquitination of IκBα, the inhibitor of NF-κB. Ubiquitinated IκBα is then rapidly degraded, allowing nuclear translocation of NF-κB subunits and gene transactivation. NEMO functions as a scaffold within the IKK complex that is required for canonical IKK enzymatic activity and NF-κB activation (3).Activation of TNF, IL-1R, and Toll-like receptor (TLR) family receptors leads to K63 and linear (also termed M1) ubiquitination of cytosolic adapter proteins, such as receptor interacting protein 1 (RIP1). This in turn promotes recruitment of the IKK complex to the receptor signaling complex (4-8). A well-known negative regulator of NF-κB activation is A20 (encoded by the gene TNFAIP3). In the TNF-R1 complex, A20 removes K63-linked ubiquitin modifications on RIP1 through its deubiquitinase activity and converts these to K48-linked polyubiquitin chains through its E3 ligase activity (9). Editing of polyubiquitin linkages at the receptor complex in this manner results in rapid degradation of RIP1 and other signaling proteins, such as TRAF6, TRAF2, cIAP1, and cIAP2 (9, 10), promoting the termination of receptor-induced NF-κB activation. In addition, A20 directly inhibits IKK activity independently of its deubiquitinase activity in...

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“…40 Interestingly, it was recently reported that NEMO also negatively regulates TNF-mediated RIPK1-dependent apoptosis and necroptosis independently of NF-kB. 43,44 Whether TAK1 and NEMO collaborate in the early NF-kB-independent cell death checkpoint downstream of TNFR1 by regulating RIPK1 kinase activity is an interesting possibility that will deserve future attention.…”

Section: Discussionmentioning

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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NEMO Inhibits Programmed Necrosis in an NFκB-Independent Manner by Restraining RIP1

Cited by 57 publications

References 67 publications

Brain endothelial TAK1 and NEMO safeguard the neurovascular unit

Brain endothelial TAK1 and NEMO safeguard the neurovascular unit

Recruitment of A20 by the C-terminal domain of NEMO suppresses NF-κB activation and autoinflammatory disease

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

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