Holding RIPK1 on the Ubiquitin Leash in TNFR1 Signaling

Peltzer, Nieves; Darding, Maurice; Walczak, Henning

doi:10.1016/j.tcb.2016.01.006

Cited by 148 publications

(130 citation statements)

References 112 publications

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“…Apoptosis occurs through two pathways: the extrinsic pathway, which is activated by extracellular ligands (for example, Tumour Necrosis Factor Alpha, TNF α ) that bind to death receptors; and the intrinsic pathway, which is engaged by cellular stress (for example, terminal Unfolded Protein Response activated by Tunicamycin, Tn, or Thapsigargin, Tg). 14, 15, 16, 17 …”

Section: Resultsmentioning

confidence: 99%

Robust high-throughput kinetic analysis of apoptosis with real-time high-content live-cell imaging

Gelles

Chipuk

2016

Cell Death Dis

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Quantitative and kinetic analyses of apoptotic cell death are integral components of exploring cell biology, measuring cellular stress responses, and performing high-throughput genomic/RNAi/drug screens. Here, we present a detailed method that integrates robust kinetic real-time high-content imaging with Annexin V labelling to provide a highly sensitive, accurate, simple and zero-handling approach to quantify extrinsic and intrinsic inducers of apoptosis. The sensitivity of this non-toxic method outperforms previous high-throughput methodologies using viability dyes or caspase-activation reporters. This method also incorporates a multiplex adaptation to integrate variability in cell number due to treatment-induced proliferation changes and the detachment of dying cells. Compared to Annexin V detection by flow cytometry, this method is 10-fold more sensitive, eliminates extensive sample handling and processing, and provides real-time kinetics of apoptosis at both single-cell and population-level resolutions.

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Section: Resultsmentioning

confidence: 99%

Robust high-throughput kinetic analysis of apoptosis with real-time high-content live-cell imaging

Gelles

Chipuk

2016

Cell Death Dis

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“…Since defects in NF-κB are known to sensitize cells to TNF-induced cell death (Peltzer et al., 2016), we examined whether inhibition of MK2 affected TNF-induced activation of NF-κB and MAPK. However, inhibition or deletion of MK2 had no effect on TNF-induced degradation of IκBα or phosphorylation of p65, JNK, or ERK in MEFs and BMDMs (Figures 4A and 4B).…”

Section: Resultsmentioning

confidence: 99%

MK2 Phosphorylates RIPK1 to Prevent TNF-Induced Cell Death

et al. 2017

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SummaryTNF is an inflammatory cytokine that upon binding to its receptor, TNFR1, can drive cytokine production, cell survival, or cell death. TNFR1 stimulation causes activation of NF-κB, p38α, and its downstream effector kinase MK2, thereby promoting transcription, mRNA stabilization, and translation of target genes. Here we show that TNF-induced activation of MK2 results in global RIPK1 phosphorylation. MK2 directly phosphorylates RIPK1 at residue S321, which inhibits its ability to bind FADD/caspase-8 and induce RIPK1-kinase-dependent apoptosis and necroptosis. Consistently, a phospho-mimetic S321D RIPK1 mutation limits TNF-induced death. Mechanistically, we find that phosphorylation of S321 inhibits RIPK1 kinase activation. We further show that cytosolic RIPK1 contributes to complex-II-mediated cell death, independent of its recruitment to complex-I, suggesting that complex-II originates from both RIPK1 in complex-I and cytosolic RIPK1. Thus, MK2-mediated phosphorylation of RIPK1 serves as a checkpoint within the TNF signaling pathway that integrates cell survival and cytokine production.

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“…TRADD in turns recruits a group of proteins including TRAFs, cIAPs, RIPK1, HOIP, HOIL-1L and Sharpin to form complex I which induces the NF-κB signaling. Ubiquitination of RIPK1 is critical for the dissociation of the complex I from TNFR1 providing two types of complex II (Peltzer, Darding, & Walczak, 2016). In the complex IIa FADD and procaspase-8 are assembled to induce apoptosis.…”

Section: Dubs In Regulation Of Apoptosis Pathways In Cancersmentioning

confidence: 99%

Emerging role of DUBs in tumor metastasis and apoptosis: Therapeutic implication

Zhou

et al. 2017

Pharmacology & Therapeutics

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Malfunction of ubiquitin-proteasome system is tightly linked to tumor formation and tumor metastasis. Targeting the ubiquitin-pathway provides a new strategy for anti-cancer therapy. Despite the parts played by ubiquitin modifiers, removal of ubiquitin from the functional proteins by the deubiquitinating enzymes (DUBs) plays an important role in governing the multiple steps of the metastatic cascade, including local invasion, dissemination, and eventual colonization of the tumor to distant organs. Both deregulated ubiquitination and deubiquitination could lead to dysregulation of various critical events and pathways such as apoptosis and epithelial-mesenchymal transition (EMT). Recent TCGA study has further revealed the connection between mutations of DUBs and various types of tumors. In addition, emerging drug design targeting DUBs provides a new strategy for anti-cancer therapy. In this review, we will summarize the role of deubiquitination and highlight the recent discoveries of DUBs with regards to multiple metastatic events including anti-apoptosis pathway and EMT. We will further discuss the regulation of deubiquitination as a novel strategy for anti-cancer therapy.

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Holding RIPK1 on the Ubiquitin Leash in TNFR1 Signaling

Cited by 148 publications

References 112 publications

Robust high-throughput kinetic analysis of apoptosis with real-time high-content live-cell imaging

Robust high-throughput kinetic analysis of apoptosis with real-time high-content live-cell imaging

MK2 Phosphorylates RIPK1 to Prevent TNF-Induced Cell Death

Emerging role of DUBs in tumor metastasis and apoptosis: Therapeutic implication

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