Broemer, M., Tenev, T., Rigbolt, K. T. G., Hempel, S., Blagoev, B., Silke, J., Ditzel, M., Meier, P. (2010) Systematic In Vivo RNAi Analysis Identifies IAPs as NEDD8-E3 Ligases. MOLECULAR CELL, 40 (5). pp. 810-822. ISSN 1097-2765

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Abstract

The intimate relationship between mediators of the ubiquitin (Ub)-signaling system and human diseases has sparked profound interest in how Ub influences cell death and survival. While the consequence of Ub attachment is intensely studied, little is known with regards to the effects of other Ub-like proteins (UBLs), and deconjugating enzymes that remove the Ub or UBL adduct. Systematic in vivo RNAi analysis identified three NEDD8-specific isopeptidases that, when knocked down, suppress apoptosis. Consistent with the notion that attachment of NEDD8 prevents cell death, genetic ablation of deneddylase 1 (DEN1) suppresses apoptosis. Unexpectedly, we find that Drosophila and human inhibitor of apoptosis (IAP) proteins can function as E3 ligases of the NEDD8 conjugation pathway, targeting effector caspases for neddylation and inactivation. Finally, we demonstrate that DEN1 reverses this effect by removing the NEDD8 modification. Altogether, our findings indicate that IAPs not only modulate cellular processes via ubiquitylation but also through attachment of NEDD8, thereby extending the complexity of IAP-mediated signaling.

Item Type:	Article
Authors (ICR Faculty only):	Meier, Pascal and Tenev, Tencho
All Authors:	Broemer, M., Tenev, T., Rigbolt, K. T. G., Hempel, S., Blagoev, B., Silke, J., Ditzel, M., Meier, P.
Uncontrolled Keywords:	UBIQUITIN-LIKE PROTEINS; PROGRAMMED CELL-DEATH; X-LINKED INHIBITOR; KAPPA-B-ALPHA; DEUBIQUITINATING ENZYMES; TRANSCRIPTIONAL ACTIVITY; REGULATING APOPTOSIS; DISTINCT MECHANISMS; CONJUGATION PATHWAY; EFFECTOR CASPASES
Funding Acknowledgement:	Deutsche Forschungsgemeinschaft ; Breakthrough ; National Health Service
Funding Text:	We would like to thank Millenium Pharmaceuticals for MLN4924 compound. We thank members of the Meier Lab for support and critical reading of the manuscript. In particular, we would like to thank Mariam Orme for advice with fly genetics, Markets Zvelebil for help with bioinformatics, and Helen Walden for support in structural information. M.B. is supported by a fellowship of the Deutsche Forschungsgemeinschaft and Breakthrough. We acknowledge National Health Service funding to the National Institute for Health Research Biomedical Research Centre.
Research teams:	ICR divisions > Breast Cancer Research > Apoptosis
Depositing User:	Users 10 not found.
Date Deposited:	21 Jan 2011 10:00
Last Modified:	21 Jan 2011 10:00
URI:	http://publications.icr.ac.uk/id/eprint/10300

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