IAPs contain an evolutionarily conserved ubiquitin-binding domain that regulates NF-κB as well as cell survival and oncogenesis

Gyrd‐Hansen, Mads; Darding, Maurice; Miasari, Maria; Santoro, Massimo; Zender, Lars; Xue, Wen; Tenev, Tencho; Fonseca, Paula C. A. da; Zvelebil, Marketa; Bujnicki, Janusz M.; Lowe, Scott W.; Silke, John; Meier, Pascal

doi:10.1038/ncb1789

Cited by 230 publications

(199 citation statements)

References 40 publications

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“…They further proposed that the UBA domain of the cIAP2/MALT1 fusion mediates constitutive activation of NF-kB by interacting with polyubiquitinated NEMO. 109 In contrast, Blankenship et al found that cIAP1 bound mono-, K48-linked, and K63-linked ubiquitin. Mutating the UBA domains also attenuated the antiapoptotic activity of cIAP1/ 2, but they ruled out a role for UBAs for modulating cIAPmediated NF-kB activation because mutations in the ubiquitin-binding region failed to impair cIAP-mediated NF-kB activation.…”

Section: Fadd-mediated Dr Signaling: Fas/dr4/dr5mentioning

confidence: 99%

Regulation of death receptor signaling by the ubiquitin system

Wertz¹,

Dixit²

2009

Cell Death Differ

109

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The study of death receptor (DR) signaling has led to the discovery of new signaling paradigms, including the first example of direct receptor-mediated activation of a protease (caspase-8) that functions as a second messenger to initiate a 'death cascade' of downstream protease activation. More recently, this receptor system has underscored the importance of ubiquitin modification in NF-jB activation. Both degradative lysine 48-linked polyubiquitin and scaffolding lysine 63-linked polyubiquitin have an essential role in signal propagation. Remarkably, a negative feedback process, termed ubiquitin editing, regulates signaling that emanates from certain DRs. Ubiquitin editing is mediated by a complex interplay between the ubiquitination and deubiquitination machinery, resulting in the replacement of signal enhancing lysine 63-linked polyubiquitin with signal extinguishing lysine 48-linked polyubiquitin. The ubiquitination machinery and its regulation in the context of DR signaling are discussed herein. The tumor necrosis factor receptor (TNFR) family is characterized by the presence of a variable number of cysteinerich domains within the extracellular segment and includes receptors known as the death receptors (DRs). The cognate ligands function in concert with the receptors to orchestrate immune responses, generate secondary lymphoid organs, and modulate the survival, proliferation, and differentiation of responding cells. When this axis goes awry, it can contribute to sepsis, cachexia, and autoimmune disorders including rheumatoid arthritis, inflammatory bowel disease, and psoriasis. 1,2 Indeed, therapeutics based on neutralization of tumor necrosis factor-a (TNF-a) have met unparalleled success in the treatment of many autoimmune disorders. Furthermore, there has been a recent groundswell of enthusiasm for exploiting the proapoptotic properties of the DRs for TRAIL/ Apo2 ligand that selectively mediate the demise of tumor cells.There are six TNFR family DRs identified in humans to date: Fas/CD-95, TNFR1, DR3, DR4, DR5, and DR6. They are characterized by the presence of an B80-residue motif within their cytosolic segments dubbed the death domain (DD). 1,2 The integrity of this domain is essential for engaging downstream signaling components that, depending on the cellular context, promote either prosurvival and proinflammatory signaling pathways or promote apoptosis. 1,2 The DD is sixhelical fold that adopts a 'Greek key' topology and mediates homotypic interactions. There are four death-fold motifs: the DD itself, the death effector domain (DED), caspase activation and recruitment domain (CARD), and the Pyrin domain. 3 Although these folds all possess a similar topological configuration, their surface charge is distinct such that specificity of association is dictated by electrostatic interactions. 3 The DRs initiate signaling by recruiting one of two DD-containing platform adaptor molecules: FADD (Fas Associated Death Domain) that generally mediates apoptosis and/or TRADD (TNF Receptor Associated Death Domain)...

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Section: Fadd-mediated Dr Signaling: Fas/dr4/dr5mentioning

confidence: 99%

Regulation of death receptor signaling by the ubiquitin system

Wertz¹,

Dixit²

2009

Cell Death Differ

109

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“…The mammalian IAPs that regulate cell survival, cIAP1, cIAP2 and XIAP, harbour three BIR domains. In addition, these IAPs contain a UBA (ubiquitin (Ub)-associated domain) domain that enables them to bind to polyubiquitin chains 9,10 as well as a RING (Really Interesting New Gene) domain that provides them with Ub E3 ligase activity. 11 cIAP1 and cIAP2 also contain a CARD (caspase recruitment domain) that is required to shut-down cIAP1's E3 ligase activity under steady-state conditions.…”

Section: Open Questionsmentioning

confidence: 99%

IAPs: Guardians of RIPK1

Darding

Meier

2011

Cell Death Differ

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“…XIAP consists of three BIR domains (baculoviral IAP repeat 1-3), a RING-finger domain conferring ubiquitin (Ub) protein ligase (E3) activity and a recently discovered evolutionarily conserved Ub-acceptor (UBA) domain (Gyrd-Hansen et al, 2008;Srinivasula and Ashwell, 2008). XIAP was identified as the only cellular protein being able to bind caspase-3, -7 and -9 directly and to inhibit both the initiation and the execution phase of apoptosis (Deveraux et al, 1999).…”

Section: Introductionmentioning

confidence: 99%

Caspase-3 cleaves XIAP in a positive feedback loop to sensitize melanoma cells to TRAIL-induced apoptosis

et al. 2010

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Successful treatment of melanoma is still challenging, because metastasis remain chemoresistant and radioresistant. Accordingly, combinational treatments involving death ligands are mandatory. In a recent study from our lab, the majority out of 18 melanoma cell lines remained resistant against treatment with the death ligand TRAIL (tumor necrosis factor related apoptosis inducing ligand). Resistance was shown to be mainly due to incomplete processing of caspase-3 into catalytically inactive p21 by binding of the anti-apoptotic protein X-linked inhibitor of apoptosis protein (XIAP). Coirradiation with sub-lethal ultraviolet (UV) B caused depletion of XIAP resulting in synergistic sensitization of all but two melanoma cell lines to TRAIL. We show here the XIAP depletion to essentially require initial caspasemediated cleavage, which promotes proteasomal degradation of XIAP. Utilizing specific caspase inhibitors and small interfering RNA-mediated knockdown, we further identified caspase-3 to be responsible for performing the initial cleavage of XIAP after UVB treatment. Additional evidence suggests an accelerated mitochondrial outer membrane permeabilization in response to co-treatment with TRAIL and UVB, which directs the release of XIAP antagonizing factors including Smac. Distraction of XIAP consequently liberates caspase-3 to autocatalytically process into active p17. Activated caspase-3 cleaves XIAP and further enhances its activation in a positive regulatory feedback loop. The molecular mechanism discovered here appears to have broader implications, because cleavage of XIAP was also shown to accompany cisplatin-induced sensitization of melanoma cells to TRAIL.

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IAPs contain an evolutionarily conserved ubiquitin-binding domain that regulates NF-κB as well as cell survival and oncogenesis

Cited by 230 publications

References 40 publications

Regulation of death receptor signaling by the ubiquitin system

Regulation of death receptor signaling by the ubiquitin system

IAPs: Guardians of RIPK1

Caspase-3 cleaves XIAP in a positive feedback loop to sensitize melanoma cells to TRAIL-induced apoptosis

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