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

Lee, Eun Woo; Kim, Jung Hoon; Ahn, Yeong Hee; Seo, Jinho; Ko, Aram; Jeong, Min-Ji; Kim, Seok Jun; Ro, Jae Y.; Park, Ki Moon; Lee, Han Woong; Park, Eun Jung; Chun, Kyung–Hee; Song, Jaewhan

doi:10.1038/ncomms1981

Cited by 105 publications

(87 citation statements)

References 56 publications

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“…Interestingly, FADD-depleted cells formed a more RIP1/RIP3 necrosome complex upon TNF activation in the presence of caspase inhibitor (72). Since FADD can bind to RIP1 and RIP3, FADD might directly modulate the interaction between RIP1 and RIP3 (72,79). Thus, we cannot exclude the idea that FADD might have caspase-8-independent role as well as caspase-8-dependent role in necroptosis.…”

Section: Proposed Mechanisms By Which Fadd Regulates Necroptosis In Amentioning

confidence: 61%

“…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. 2G versus 2D) (72). Since FADD is required for the activation of caspase-8, which is able to suppress necroptosis, FADD-deficient cells facilitate necroptotic cell death by abrogating caspase-8 function (Fig.…”

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

confidence: 99%

“…Since many studies have analyzed the roles of FADD in necroptosis under caspase inhibition using zVAD-fmk, and pan-caspase inhibitor, the presence and absence of FADD will not affect caspase-8 activity. Interestingly, FADD-depleted cells formed a more RIP1/RIP3 necrosome complex upon TNF activation in the presence of caspase inhibitor (72). Since FADD can bind to RIP1 and RIP3, FADD might directly modulate the interaction between RIP1 and RIP3 (72,79).…”

Section: Proposed Mechanisms By Which Fadd Regulates Necroptosis In Amentioning

confidence: 99%

“…Rather, it seems to be involved in cell cycle regulation (3)(4)(5)(6)(7)(8). Recently, we determined that FADD turnover is mediated by MKRN1-mediated ubiquitination, affecting DR-induced apoptosis in vitro and in vivo (72).…”

Section: Regulation Of Extrinsic Apoptosismentioning

confidence: 99%

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The roles of FADD in extrinsic apoptosis and necroptosis

et al. 2012

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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...

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Section: Proposed Mechanisms By Which Fadd Regulates Necroptosis In Amentioning

confidence: 61%

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

confidence: 99%

Section: Proposed Mechanisms By Which Fadd Regulates Necroptosis In Amentioning

confidence: 99%

Section: Regulation Of Extrinsic Apoptosismentioning

confidence: 99%

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The roles of FADD in extrinsic apoptosis and necroptosis

et al. 2012

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“…Like other Mkrns, LEP-2 has a RING domain that is typical of many E3 ligases (Bohne et al, 2010;Gray et al, 2000). Indeed, Mkrn1 in mammals functions as an E3 ligase, targeting several proteins and even itself, although has not yet been identified as one of its targets (Kim et al, 2005;Salvatico et al, 2010;Lee et al, 2009Lee et al, , 2012Ko et al, 2012;Shimada et al, 2009;Ko et al, 2010;Kim et al, 2014;Cassar et al, 2015). In other contexts, Mkrns are also RNA-binding proteins, are localized to ribonucleoprotein granules, and have been found to sequester some mRNAs or promote their translation (Cano et al, 2010;Cassar et al, 2015;Gajdos et al, 2010;Kwon et al, 2013;Miroci et al, 2012;Cheung et al, 2010;Yang et al, 2008).…”

Section: Discussionmentioning

confidence: 99%

LEP-2/Makorin regulates LIN-28 stability to promote the juvenile-to-adult transition in Caenorhabditis elegans

2016

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The heterochronic genes lin-28, let-7 and lin-41 regulate fundamental developmental transitions in animals, such as stemness versus differentiation and juvenile versus adult states. We identify a new heterochronic gene, lep-2, in Caenorhabditis elegans. Mutations in lep-2 cause a delay in the juvenile-to-adult transition, with adult males retaining pointed, juvenile tail tips, and displaying defective sexual behaviors. In both sexes, lep-2 mutants fail to cease molting or produce an adult cuticle. We find that LEP-2 post-translationally regulates LIN-28 by promoting LIN-28 protein degradation. lep-2 encodes the sole C. elegans ortholog of the Makorin (Mkrn) family of proteins. Like lin-28 and other heterochronic pathway members, vertebrate Mkrns are involved in developmental switches, including the timing of pubertal onset in humans. Based on shared roles, conservation and the interaction between lep-2 and lin-28 shown here, we propose that Mkrns, together with other heterochronic genes, constitute an evolutionarily ancient conserved module regulating switches in development.

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Death Receptors

Krammer

Pietkiewicz

Lavrik

2016

Encyclopedia of Life Sciences

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Apoptosis, or programmed cell death, is a common property of all multicellular organisms and maintains essential cellular homeostasis in tissues by balancing cell renewal and removal of mutated or old cells. It can be triggered by a number of factors including ultraviolet (UV) or γ‐irradiation, chemotherapeutic drugs or growth factor withdrawal. A death signal can either be induced by the activation of death receptors (DRs, extrinsic pathway) or via the mitochondria (intrinsic pathway). The DR family is a subfamily of the tumour necrosis factor receptor (TNFR) superfamily. Stimulation of the DRs results in the formation of high‐molecular‐weight protein complexes that transduce apoptotic, necroptotic or survival signals. Key Concepts Stimulation of the death receptors (DRs) leads to apoptosis, necroptosis or NF‐κB activation. All DRs are distinguished by the presence of the death domain (DD). Cross‐linking of DR with death ligands results in the formation of the death‐inducing signalling complex (DISC). Caspases play the central role in the transduction of DR‐induced apoptotic signal. Procaspase‐8 is activated at the death effector domain (DED) chains at the DISC. c‐FLIP proteins block or promote caspase‐8 activation at the DISC depending on their amount at the receptor complex and thereby regulate DR‐induced apoptosis. Stimulation of DR might lead to the induction of receptor‐interacting protein kinase 1 and 3 (RIPK1‐ and RIPK3)‐mediated nonapoptotic cell death, necroptosis. Apoptosis and necroptosis are triggered by high‐molecular‐weight protein complexes consisting of similar proteins.

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

Cited by 105 publications

References 56 publications

The roles of FADD in extrinsic apoptosis and necroptosis

The roles of FADD in extrinsic apoptosis and necroptosis

LEP-2/Makorin regulates LIN-28 stability to promote the juvenile-to-adult transition in Caenorhabditis elegans

Death Receptors

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