TNF-induced necroptosis in L929 cells is tightly regulated by multiple TNFR1 complex I and II members

Vanlangenakker, Nele; Bertrand, Mathieu J.M.; Bogaert, Pieter; Vandenabeele, Peter; Berghe, Tom Vanden

doi:10.1038/cddis.2011.111

Cited by 206 publications

(231 citation statements)

References 41 publications

Supporting

Mentioning

200

Contrasting

Unclassified

Order By: Relevance

“…To determine the exact function of FADD in necrosome formation in relation to MKRN1, we first depleted FADD in L929 and HT-29 cells. Consistent with a previous report 44 , knockdown of FADD significantly induced necroptosis in both cell types ( Fig. 5e; Supplementary Fig.…”

Section: Fadd Stabilization Upon Mkrn1 Depletion Prevents Necroptosissupporting

confidence: 93%

Ubiquitination and degradation of the FADD adaptor protein regulate death receptor-mediated apoptosis and necroptosis

et al. 2012

View full text Add to dashboard Cite

Fas-associated protein with death domain (FADD) is a pivotal component of death receptormediated extrinsic apoptosis and necroptosis. Here we show that FADD is regulated by makorin Ring Finger Protein 1 (mKRn1) E3 ligase-mediated ubiquitination and proteasomal degradation. mKRn1 knockdown results in FADD protein stabilization and formation of the rapid deathinducing signalling complex, which causes hypersensitivity to extrinsic apoptosis by facilitating caspase-8 and caspase-3 cleavage in response to death signals. We also show that mKRn1 and FADD are involved in the regulation of necrosome formation and necroptosis upon caspase inhibition. Downregulation of mKRn1 results in severe defects of tumour growth upon tumour necrosis factor-related apoptosis-inducing ligand treatment in a xenograft model using mDAmB-231 breast cancer cells. suppression of tumour growth by mKRn1 depletion is relieved by simultaneous FADD knockdown. our data reveal a novel mechanism by which fas-associated protein with death domain is regulated via an ubiquitination-induced degradation pathway. A poptosis, or programmed cell death, can be initiated by intrinsic or extrinsic pathways 1,2 . Intrinsic pathways are triggered by mitochondrial permeabilization, which results in the release of cytochrome c and the formation of an apoptosome complex, leading to caspase-9 activation 3 . Extrinsic pathways can be induced by activation of death receptors (DRs), such as TNFR1, tumour necrosis factor-related apoptosis-inducing ligand (TRAIL) receptors and Fas/CD95 by their corresponding ligands; receptor activation triggers the formation of the death-inducing signalling complex (DISC) or TNFR complex II, which comprises caspase-8 and fas-associated protein with death domain (FADD). These complexes ultimately activate caspase-8, thereby causing extrinsic apoptosis 3,4 . In addition to inducing extrinsic apoptosis, caspase-8 and FADD are known to suppress necroptosis under various conditions [5][6][7][8][9][10][11] .DR downstream pathways are regulated in various ways. For example, cFLIP (cellular FLICE inhibitory protein) competes with caspase-8 for binding to FADD, preventing DISC formation 12 . The levels and activities of cFLIP are controlled by numerous factors including NF-κB, Akt, JNK, Srk and ITCH [13][14][15][16][17] . CARP-1 and -2, which are E3 ubiquitin ligases for caspase-8, are also known to suppress TRAIL activation 18 . Post-translational modifications such as O-glycosylation, S-nitrosylation and S-palmitoylation of DRs have also been identified to regulate death signalling 19 . However, phosphorylation of FADD, the only post-translational modification that FADD is known to undergo, is not involved in the induction of apoptosis. Rather, this modification seems to be essential for the pro-survival roles of nuclear-localized phospho-FADD [20][21][22][23] . Other post-translational modifications affecting the apoptotic and necroptotic activities of FADD have yet to be identified.Here, we show that Makorin Ring Finger Protein 1 (MKRN1), an...

show abstract

Section: Fadd Stabilization Upon Mkrn1 Depletion Prevents Necroptosissupporting

confidence: 93%

Ubiquitination and degradation of the FADD adaptor protein regulate death receptor-mediated apoptosis and necroptosis

et al. 2012

View full text Add to dashboard Cite

show abstract

“…A study using L929 cells with FADD knockdown by shRNA showed FADD depletion induced necroptosis ( Fig. 2F) (90). We also recently reported that siRNA-or shRNA-mediated knockdown of FADD in L929 and HT-29 cells resulted in an increase in RIP1-RIP3 necrosome formation and necroptosis in the presence of caspase inhibitor, whereas FADD overexpression in L929 cells delayed RIP1-RIP3 necrosome formation and necroptosis (Fig.…”

Section: The Roles Of Fadd On Apoptosis and Necroptosis In Vitro And supporting

confidence: 60%

“…As a critical role of FADD in caspase-8 activation, FADD deficiency is thought to lead to necroptosis by inhibiting caspase-8 function. Supporting this idea, FADD deficiency abrogated caspase-8 activity and resulted in necroptosis (90). However, FADD's functions on various stimuli-induced necroptosis are contradictory; it seems to be dependent of stimuli.…”

Section: Proposed Mechanisms By Which Fadd Regulates Necroptosis In Amentioning

confidence: 94%

“…CYLD is required for necroptosis induction by deubiquitinating RIP1, whereas the involvements of other deubiquitinating enzymes that trigger RIP1 deubiquitination such as A20, USP21 and cezanne in necroptosis induction are currently unknown (46)(47)(48)86). Inhibition of cIAP function, which is critical for RIP1 polyubiquitination, by genetic deletion or pharmacological methods, has been reported to sensitize cells to necroptotic cell death by preventing RIP1 K63-linked ubiquitination (49,78,(87)(88)(89)(90). RIP1 deubiquitination leads to the formation of complex II, which is composed of TRADD, FADD, RIP1 and caspase-8 (91).…”

Section: Mechanism Of Tnf-induced Necroptosismentioning

confidence: 99%

See 1 more Smart Citation

The roles of FADD in extrinsic apoptosis and necroptosis

et al. 2012

View full text Add to dashboard Cite

Fas-associated protein with death domain (FADD), an adaptor that bridges death receptor signaling to the caspase cascade, is indispensible for the induction of extrinsic apoptotic cell death. Interest in the non-apoptotic function of FADD has greatly increased due to evidence that FADD-deficient mice or dominant-negative FADD transgenic mice result in embryonic lethality and an immune defect without showing apoptotic features. Numerous studies have suggested that FADD regulates cell cycle progression, proliferation, and autophagy, affecting these phenomena. Recently, programmed necrosis, also called necroptosis, was shown to be a key mechanism that induces embryonic lethality and an immune defect. Supporting these findings, FADD was shown to be involved in various necroptosis models. In this review, we summarize the mechanism of extrinsic apoptosis and necroptosis, and discuss the in vivo and in vitro roles of FADD in necroptosis induced by various stimuli.[BMB Reports 2012; 45(9): 496-508] INTRODUCTIONFas-associated protein with death domain (FADD) is a critical adaptor protein for death receptor (DR)-mediated apoptosis. FADD is composed of two domains called the death domain (DD) and death effector domain (DED). The DD of FADD binds to the DD of the death receptor and FADD recruits procaspase-8 through the DED-DED interaction, forming a death-inducing signaling complex (DISC), where procaspase-8 is activated by self-cleavage. Active caspase-8 cleaves downstream effector caspases such as caspase-3, -6, and -7, inducing apoptosis. Interestingly, FADD deficiency results in embryonic lethality, displaying a defect in immune homeostasis and immune cell proliferation despite the defect in inducing apoptosis. In addition, FADD is also implicated in non-apoptotic functions such as cell cycle progression, proliferation, autophagy, inflammation and innate immunity (1, 2). Particularly, FADD phosphorylation at Ser194 (pFADD) by several kinases is associated with its nuclear localization and cell cycle regulation (3-8). Although FADD and pFADD are often overexpressed in various tumors, their functions in cancer development or chemotherapy-sensitivity are still controversial (9-14). Recent strong evidence from in vivo mice studies suggested negative roles of FADD in RIP1-and RIP3-dependent necroptosis (15-18). DR-mediated caspase-8 activation requires FADD, and leads to the cleavage of RIP1, RIP3, and CYLD, preventing necroptosis (19)(20)(21)(22). Thus, FADD deficiency is thought to inhibit caspase-8 and subsequent apoptosis, but activate necroptosis. Since necroptosis can be initiated by various stimuli in a variety of cell types independently of DRs, the exact mechanisms and functions of FADD require further investigation. This review focuses on the recent discoveries about the roles of FADD in apoptosis and necroptosis in various models, and we refer the reader to two comprehensive reviews of the diverse functions of FADD (1, 2). EXTRINSIC APOPTOSIS Molecular mechanism of extrinsic apoptosisExtrinsic apoptosis, which is...

show abstract

“…This was evident when we used the L-929 clones. Inhibiting caspase-3 or caspase-8 in the cells that were dying after only 3 h of incubation with Tag7-Hsp70 complex led to their death after 20 h. Based on recent publications, caspase-8-dependent cleavage of the RIP1 kinase is considered to play the main role in inhibiting necroptosis (30). It has been shown that caspase-3 cleaves RIP1 at multiple sites in vitro but is incapable of cleaving it in vivo (21).…”

Section: Discussionmentioning

confidence: 99%

Tag7 (PGLYRP1) in Complex with Hsp70 Induces Alternative Cytotoxic Processes in Tumor Cells via TNFR1 Receptor

Yashin

Ivanova

Soshnikova

et al. 2015

Journal of Biological Chemistry

View full text Add to dashboard Cite

Background:A complex containing an innate immunity protein Tag7, and Hsp70 kills various cancer cells. Results: Tag7 and its complex with Hsp70 bind to the TNFR1 receptor, but only the Tag7-Hsp70 complex induces a cytotoxic effect via apoptosis and necroptosis. Conclusion: A new ligand has been found for the TNFR1 death receptor. Significance: Tag7 may be used as an inhibitor of the TNF-␣-induced cytotoxicity.

show abstract

TNF-induced necroptosis in L929 cells is tightly regulated by multiple TNFR1 complex I and II members

Cited by 206 publications

References 41 publications

Ubiquitination and degradation of the FADD adaptor protein regulate death receptor-mediated apoptosis and necroptosis

Ubiquitination and degradation of the FADD adaptor protein regulate death receptor-mediated apoptosis and necroptosis

The roles of FADD in extrinsic apoptosis and necroptosis

Tag7 (PGLYRP1) in Complex with Hsp70 Induces Alternative Cytotoxic Processes in Tumor Cells via TNFR1 Receptor

Contact Info

Product

Resources

About