Cited by 1,218Cell death mechanisms and regulationNF-κB Signaling PathwaysUbiquitin and proteasome pathways

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IAP Antagonists Induce Autoubiquitination of c-IAPs, NF-κB Activation, and TNFα-Dependent Apoptosis

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Varfolomeev, Eugene, Blankenship, John W., Wayson, Sarah M., Fedorova, Anna V., Kayagaki, Nobuhiko, Garg, Parie, Zobel, Kerry, Dynek, Jasmin N., Elliott, Linda O., Wallweber, Heidi J.A., Flygare, John A., Fairbrother, Wayne J., Deshayes, Kurt, Dixit, Vishva M., Vucic, Domagoj·2007·Cell

DOI 10.1016/j.cell.2007.10.030

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Abstract

Inhibitor of apoptosis (IAP) proteins are antiapoptotic regulators that block cell death in response to diverse stimuli. They are expressed at elevated levels in human malignancies and are attractive targets for the development of novel cancer therapeutics. Herein, we demonstrate that small-molecule IAP antagonists bind to select baculovirus IAP repeat (BIR) domains resulting in dramatic induction of auto-ubiquitination activity and rapid proteasomal degradation of c-IAPs. The IAP antagonists also induce cell death that is dependent on TNF signaling and de novo protein biosynthesis. Additionally, the c-IAP proteins were found to function as regulators of NF-kappaB signaling. Through their ubiquitin E3 ligase activities c-IAP1 and c-IAP2 promote proteasomal degradation of NIK, the central ser/thr kinase in the noncanonical NF-kappaB pathway.

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BackgroundMethod
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Background
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“RIPK1 phosphorylation was stimulated in the MEFs by their treatment for 3 h with TNF (1000 U/ml), together with the bivalent IAP (inhibitor of apoptosis protein) antagonist BV6 [51] and the caspase inhibitor z-VAD-fmk (both from WuXi AppTec) at concentrations of 1 and 20 μM, respectively.”
Autophagy genes in myeloid cells counteract IFNγ-induced TNF-mediated cell death and fatal TNF-induced shock
Orvedahl, A., McAllaster, M. R., Sansone, A., Dunlap, B. F., Desai, C., Wang, Y., Balce, D. R., Luke, C. J., Lee, S., Orchard, R. C., et al. (2019) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1822157116 · Cited by 40
Deciphering the nonsense-mediated mRNA decay pathway to identify cancer cell vulnerabilities for effective cancer therapy
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“NIK is usually degraded in a continuous fashion by cIAP1 and cIAP2 [58] in order to block the activation of its downstream pathway, but mutations or silencing of UPF1 were shown to aberrantly cause the accumulation of NIK resulting in chemokine production and massive immune infiltration in lung IMT [56].”
Background
Site-specific ubiquitination of MLKL targets it to endosomes and targets Listeria and Yersinia to the lysosomes
Yoon, S., Bogdanov, K., & Wallach, D. (2022) · Cell Death and Differentiation · doi:10.1038/s41418-021-00924-7 · Cited by 40
Sub-lethal signals in the mitochondrial apoptosis apparatus: pernicious by-product or physiological event?
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Potent and Selective Small-Molecule Inhibitors of cIAP1/2 Proteins Reveal That the Binding of Smac Mimetics to XIAP BIR3 Is Not Required for Their Effective Induction of Cell Death in Tumor Cells
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Design, Synthesis, and Evaluation of Potent, Nonpeptidic Mimetics of Second Mitochondria-Derived Activator of Caspases
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Inhibitor of Apoptosis Proteins: Promising Targets for Cancer Therapy
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Pathophysiological Significance of Hepatic Apoptosis
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Frequent Engagement of RelB Activation Is Critical for Cell Survival in Multiple Myeloma
Cormier, F., Monjanel, H., Fabre, C., Billot, K., Sapharikas, E., Chéreau, F., Bordereaux, D., Molina, T. J., Avet‐Loiseau, H., & Baud, V. (2013) · PLoS ONE · doi:10.1371/journal.pone.0059127 · Cited by 42
The Ribonucleotide Reductase R1 Subunits of Herpes Simplex Virus 1 and 2 Protect Cells against Poly(I · C)-Induced Apoptosis
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SNIPER(TACC3) induces cytoplasmic vacuolization and sensitizes cancer cells to Bortezomib
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Light-Controllable PROTACs for Temporospatial Control of Protein Degradation
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Recapitulating Cholangiopathy-Associated Necroptotic Cell Death In Vitro Using Human Cholangiocyte Organoids
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“In contrast, apoptosis involves activation of the noncanonical NF-kB pathway induced by TNF-a and Smac mimetic signaling.(27) We reasoned that distinct activation of NF-kB signaling might be observed in apoptotic and necroptotic hICOs.”
Background
The IAP antagonist birinapant enhances chimeric antigen receptor T cell therapy for glioblastoma by overcoming antigen heterogeneity
Song, E. Z., Wang, X., Philipson, B. I., Zhang, Q., Thokala, R., Zhang, L., Assenmacher, C., Binder, Z. A., Ming, G., O’Rourke, D. M., et al. (2022) · Molecular Therapy — Oncolytics · doi:10.1016/j.omto.2022.11.004 · Cited by 41
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“, 1995) and play important roles in TNFmediated induction of NF-jB signaling (Petersen et al., 2007; Varfolomeev et al., 2007).”
Background
Targeting Apoptosis Signaling Pathways for Anticancer Therapy
Fulda, S. (2011) · Frontiers in Oncology · doi:10.3389/fonc.2011.00023 · Cited by 38
“…engage cell death pathways by initiating autoubiquitination of cIAPs leading to activation of non-canonical NF-κB and TNFα-mediated apoptosis (Petersen et al., 2007; Varfolomeev et al., 2007; Vince et al., 2007). www.frontiersin.org August 2011 | Volume 1 | Article 23 | 5 and Ashkenazi, A. (2001).”
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The structure of XIAP BIR2: understanding the selectivity of the BIR domains
Lukacs, C., Belunis, C. J., Crowther, R. L., Danho, W., Gao, L., Goggin, B. S., Janson, C. A., Li, S., Remiszewski, S., Schutt, A. D., et al. (2013) · Acta Crystallographica Section D Biological Crystallography · doi:10.1107/s0907444913016284 · Cited by 40
“Smac is a dimer in solution, and it can bind both the BIR2 and BIR3 domains of XIAP simultaneously to prevent XIAP from binding and inhibiting caspase-3, caspase-7 and caspase-9 (Du et al., 2000; Varfolomeev et al., 2007).”
Role of Smac in Determining the Chemotherapeutic Response of Esophageal Squamous Cell Carcinoma
Yang, X., Zhou, L., Huang, J., Liu, F., Yu, J., Zhan, Q., Zhang, L., & Zhao, X. (2011) · Clinical Cancer Research · doi:10.1158/1078-0432.ccr-11-0426 · Cited by 38
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“This explains why Smac mimetics or IAP antagonists, which target cIAP-1, cIAP-2, and XIAP for autoubiquitination and degradation to promote assembly of the ripoptosome (Petersen et al. 2007; Varfolomeev et al. 2007; Vince et al. 2007; Bertrand et al. 2008), can further enhance TNFinduced necrosis.”
Background
How do pleiotropic kinase hubs mediate specific signaling by TNFR superfamily members?
Schröfelbauer, B., & Hoffmann, A. (2011) · Immunological Reviews · doi:10.1111/j.1600-065x.2011.01060.x · Cited by 37
Toxicity Profile of Small-Molecule IAP Antagonist GDC-0152 Is Linked to TNF-α Pharmacology
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Background
Inhibitor of apoptosis protein (IAP) antagonists demonstrate divergent immunomodulatory properties in human immune subsets with implications for combination therapy
Knights, A. J., Fucikova, J. P., Pasam, A., Koernig, S., & Cebon, J. S. (2012) · Cancer Immunology Immunotherapy · doi:10.1007/s00262-012-1342-1 · Cited by 37
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Smac mimetics LCL161 and GDC-0152 inhibit osteosarcoma growth and metastasis in mice
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Targeting the Ubiquitin System in Glioblastoma
Scholz, N., Kurian, K. M., Siebzehnrübl, F. A., & Licchesi, J. D. F. (2020) · Frontiers in Oncology · doi:10.3389/fonc.2020.574011 · Cited by 37
Lymphotoxin β receptor mediates caspase-dependent tumor cell apoptosis in vitro and tumor suppression in vivo despite induction of NF-κB activation
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A Comprehensive Insight into Apoptosis: Molecular Mechanisms, Signaling Pathways, and Modulating Therapeutics
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ARTS binds to a distinct domain in XIAP-BIR3 and promotes apoptosis by a mechanism that is different from other IAP-antagonists
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Innate immune agonist, dsRNA, induces apoptosis in ovarian cancer cells and enhances the potency of cytotoxic chemotherapeutics
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Background
Elimination of Osteosarcoma by Necroptosis with Graphene Oxide-Associated Anti-HER2 Antibodies
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Discovery of Highly Potent Daphnane Diterpenoids Uncovers Importin-β1 as a Druggable Vulnerability in Castration-Resistant Prostate Cancer
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TRAF2 Suppresses Basal IKK Activity in Resting Cells and TNFα Can Activate IKK in TRAF2 and TRAF5 Double Knockout Cells
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A Potent Bivalent Smac Mimetic (SM-1200) Achieving Rapid, Complete, and Durable Tumor Regression in Mice
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Authors: Varfolomeev, E., Blankenship, J. W., Wayson, S. M., Fedorova, A. V., Kayagaki, N., Garg, P., Zobel, K., Dynek, J. N., Elliott, L. O., Wallweber, H. J. A., Flygare, J. A., Fairbrother, W. J., Deshayes, K., Dixit, V. M., & Vucic, D.
Affiliations: Genentech (US)
Corresponding author: Dixit, Vishva M.
Vucic, Domagoj
ORCID: Varfolomeev, Eugene
Blankenship, John W.
Fedorova, Anna V.
Kayagaki, Nobuhiko
Zobel, Kerry
Fairbrother, Wayne J.
Dixit, Vishva M.
Vucic, Domagoj
Venue: Cell
Publisher: Elsevier BV
Published: 2007-11
Volume: 131
Issue: 4
Pages: 669-681
ISSN: 0092-8674 (ISSN-L)
DOI: 10.1016/j.cell.2007.10.030
OpenAlex: W2064299413
Cited by: 1,218
References: 51
Citations by year: 2026: 28 · 2025: 24 · 2024: 39 · 2023: 45 · 2022: 41 · 2021: 60 · 2020: 59 · 2019: 54 · 2018: 69 · 2017: 64 · 2016: 78 · 2015: 80 · 2014: 100 · 2013: 78 · 2012: 71
FWCI: 33.22
Type: journal article
Language: en
Open access: bronze
doi.org
Licence: www.elsevier.com/tdm/userlicense/1.0/ (tdm)
www.elsevier.com/open-access/userlicense/1.0/ (vor, 2085 d)
Locations: Cell (publishedVersion)
PubMed (publishedVersion)
Lund University Publications (Lund University) (submittedVersion)
Funders: Genentech
Topics: Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Cell death mechanisms and regulation
Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › NF-κB Signaling Pathways
Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Ubiquitin and proteasome pathways
Keywords: inhibitor of apoptosis proteins, IAP antagonists, cIAP1, cIAP2, autoubiquitination, proteasomal degradation, NF-κB signaling, non-canonical NF-κB signaling, NIK, TNF signaling, apoptosis, cancer therapeutics
MeSH terms: Animals, Cell Line, Humans, Neoplasms, Tumor Necrosis Factor-alpha, Molecular Structure, Signal Transduction, NF-kappa B, Apoptosis, Protein Structure, Tertiary, Polyubiquitin, Proteasome Endopeptidase Complex, Inhibitor of Apoptosis Proteins, Mice, Ubiquitination

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IAP Antagonists Induce Autoubiquitination of c-IAPs, NF-κB Activation, and TNFα-Dependent Apoptosis

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