cIAP2 is a K63 ubiquitin ligase for RIP1 which is blocked by IAP BIR antagonists during death receptor-mediated apoptosis
Bibliographic record
Abstract
1557 The inhibitor of apoptosis proteins (IAPs) are important regulators of cell death in cancer and overexpression of various IAPs predicts poor patient outcome in several types of malignancy. The best-studied IAP is X-linked IAP (XIAP), which directly inhibits caspase-3, caspase-7 and caspase-9. Interestingly, other IAPs do not appear to directly block caspase activity and therefore the precise pro-survival mechanisms used by these family remains uncertain. Smac is a mitochondrial protein that, once released into the cytosol, binds to a groove in the IAP BIR3 domain present in XIAP, cIAP1 and cIAP2. The interaction of Smac with XIAP releases inhibition of caspase-9 and the N-terminal stretch of four residues in Smac that binds the BIR3 domain, AVPI, has served as a structural template for the development of XIAP antagonists. In this study, we demonstrate that AEG40730, a bridged AVPI mimetic, which binds IAP BIR3 domains with nM affinity, causes profound apoptotic sensitization to death ligands. In some cancer cell lines, treatment with AEG40730 alone results in caspase-8 dependent apoptosis and we show that this occurs through activation of a TNFα autocrine loop. RIP1 is a cytosolic adaptor protein that functions downstream of the TNF receptor which has emerged as a key element regulating apoptotic and survival signaling pathways. We show that RIP1 is constitutively ubiquinated in cancer cells and that AEG40730 treatment, by eliminating cIAP2, abolishes RIP1 ubiquination and thereby facilitates RIP1-dependent caspase-8 activation and cell death. We demonstrate that cIAP2 normally inhibits caspase-8 activation in cancer cells by functioning as an E3 ubiquitin ligase that directly mediates K63 polyubiquitin chain production on RIP1. Thus, RIP1 plays a crucial role in death receptor signaling and its switch from a pro-survival to a pro-apoptotic function is regulated via K63 ubiquitination that is induced by cIAP2. These findings provide new insights into the function of the IAPs and open new therapeutic opportunities in the treatment of cancer. * These authors contributed equally to this project. This work was supported by a grant from the Canadian Institute of Health Research (CIHR) to PAB.
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How this classification was reachedexpand
Full frame machine prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. The Gemma side is a direct model label for every work in the frame, read from the title-only record. The Codex side is a classifier learned from the 10,348 direct Codex labels and calibrated to design-weighted sample rates; fields without enough sample support carry no Codex call. Candidate is the union of the two sides; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels.
Distilled classifier scores by category (both heads)
| Category | Codex | Gemma |
|---|---|---|
| Metaresearch | 0.000 | 0.000 |
| Meta-epidemiology (narrow) | 0.000 | 0.000 |
| Meta-epidemiology (broad) | 0.000 | 0.000 |
| Bibliometrics | 0.000 | 0.000 |
| Science and technology studies | 0.000 | 0.000 |
| Scholarly communication | 0.000 | 0.000 |
| Open science | 0.000 | 0.000 |
| Research integrity | 0.000 | 0.001 |
| Insufficient payload (model declined to judge) | 0.003 | 0.001 |
Machine scores (provisional)
The two teacher heads of the student model, read on this work. A score orders the frame for review; it never asserts a category, and the validation status ships verbatim with every row.
Baseline scores from an immature model (maturity gate not passed, 7 training rounds). Scores rank; they never assert a category.
score_only:v0-immature-baseline · verbatim from the scoring run: score_only means the number may rank works, and no category label ships from itClassification
machine, unvalidatedMachine predicted; a candidate call from one source (direct Gemma or distilled Codex), not a consensus.
How this classification was reached, model by model and score by score, is at the end of the page under "How this classification was reached".