Systematic In Vivo RNAi Analysis Identifies IAPs as NEDD8-E3 Ligases

Meike Broemer, Tencho Tenev, Kristoffer T G Rigbolt, Sophie Hempel, Blagoy Blagoev, John Silke, Mark Ditzel, Pascal Meier

Publikation: Bidrag til tidsskriftTidsskriftartikelForskningpeer review

Resumé

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.
OriginalsprogEngelsk
TidsskriftMolecular Cell
Vol/bind40
Udgave nummer5
Sider (fra-til)810-822
Antal sider13
ISSN1097-2765
DOI
StatusUdgivet - 10. dec. 2010

Fingeraftryk

Ubiquitin-Protein Ligases
Ubiquitin
RNA Interference
Apoptosis
Cell Death
Ubiquitins
Cell Survival
Enzymes

Citer dette

Broemer, M., Tenev, T., Rigbolt, K. T. G., Hempel, S., Blagoev, B., Silke, J., ... Meier, P. (2010). Systematic In Vivo RNAi Analysis Identifies IAPs as NEDD8-E3 Ligases. Molecular Cell, 40(5), 810-822. https://doi.org/10.1016/j.molcel.2010.11.011
Broemer, Meike ; Tenev, Tencho ; Rigbolt, Kristoffer T G ; Hempel, Sophie ; Blagoev, Blagoy ; Silke, John ; Ditzel, Mark ; Meier, Pascal. / Systematic In Vivo RNAi Analysis Identifies IAPs as NEDD8-E3 Ligases. I: Molecular Cell. 2010 ; Bind 40, Nr. 5. s. 810-822.
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title = "Systematic In Vivo RNAi Analysis Identifies IAPs as NEDD8-E3 Ligases",
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.",
author = "Meike Broemer and Tencho Tenev and Rigbolt, {Kristoffer T G} and Sophie Hempel and Blagoy Blagoev and John Silke and Mark Ditzel and Pascal Meier",
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Broemer, M, Tenev, T, Rigbolt, KTG, Hempel, S, Blagoev, B, Silke, J, Ditzel, M & Meier, P 2010, 'Systematic In Vivo RNAi Analysis Identifies IAPs as NEDD8-E3 Ligases', Molecular Cell, bind 40, nr. 5, s. 810-822. https://doi.org/10.1016/j.molcel.2010.11.011

Systematic In Vivo RNAi Analysis Identifies IAPs as NEDD8-E3 Ligases. / Broemer, Meike; Tenev, Tencho; Rigbolt, Kristoffer T G; Hempel, Sophie; Blagoev, Blagoy; Silke, John; Ditzel, Mark; Meier, Pascal.

I: Molecular Cell, Bind 40, Nr. 5, 10.12.2010, s. 810-822.

Publikation: Bidrag til tidsskriftTidsskriftartikelForskningpeer review

TY - JOUR

T1 - Systematic In Vivo RNAi Analysis Identifies IAPs as NEDD8-E3 Ligases

AU - Broemer, Meike

AU - Tenev, Tencho

AU - Rigbolt, Kristoffer T G

AU - Hempel, Sophie

AU - Blagoev, Blagoy

AU - Silke, John

AU - Ditzel, Mark

AU - Meier, Pascal

N1 - Copyright © 2010 Elsevier Inc. All rights reserved.

PY - 2010/12/10

Y1 - 2010/12/10

N2 - 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.

AB - 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.

U2 - 10.1016/j.molcel.2010.11.011

DO - 10.1016/j.molcel.2010.11.011

M3 - Journal article

VL - 40

SP - 810

EP - 822

JO - Molecular Cell

JF - Molecular Cell

SN - 1097-2765

IS - 5

ER -