cIAP1 and cIAP2 facilitate cancer cell survival by functioning as E3 ligases that promote RIP1 ubiquitination.
The inhibitor of apoptosis (IAP) family of proteins enhances cell survival through mechanisms that remain uncertain. In this report, we show that cIAP1 and cIAP2 promote cancer cell survival by functioning as E3 ubiquitin ligases that maintain constitutive ubiquitination of the RIP1 adaptor protein. We demonstrate that AEG40730, a compound modeled on BIR-binding tetrapeptides, binds to cIAP1 and cIAP2, facilitates their autoubiquitination and proteosomal degradation, and causes a dramatic reduction in RIP1 ubiquitination. We show that cIAP1 and cIAP2 directly ubiquitinate RIP1 and induce constitutive RIP1 ubiquitination in cancer cells and demonstrate that constitutively ubiquitinated RIP1 associates with the prosurvival kinase TAK1. When deubiquitinated by AEG40730 treatment, RIP1 binds caspase-8 and induces apoptosis. These findings provide insights into the function of the IAPs and provide new therapeutic opportunities in the treatment of cancer.
Montreal Neurological Institute, McGill University, Montreal, Quebec H3A2B4, Canada.
Mathieu J M
MJ
Bertrand
Snezana
S
Milutinovic
Kathleen M
KM
Dickson
Wai Chi
WC
Ho
Alain
A
Boudreault
Jon
J
Durkin
John W
JW
Gillard
James B
JB
Jaquith
Stephen J
SJ
Morris
Philip A
PA
Barker
D000075747:Baculoviral IAP Repeat-Containing 3 Protein; D053181:Caspase 8 / Q000378:metabolism; D016923:Cell Death / Q000187:drug effects; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D004789:Enzyme Activation / Q000187:drug effects; D005260:Female; D006801:Humans; D051034:Inhibitor of Apoptosis Proteins / Q000378:metabolism*; D028861:Nuclear Pore Complex Proteins / Q000378:metabolism*; D010051:Ovarian Neoplasms; D016601:RNA-Binding Proteins / Q000378:metabolism*; D013449:Sulfonamides / Q000494:pharmacology; D025801:Ubiquitin / Q000378:metabolism*; D044767:Ubiquitin-Protein Ligases / Q000378:metabolism*
C119724:AGFG1 protein, human; D051034:Inhibitor of Apoptosis Proteins; D028861:Nuclear Pore Complex Proteins; D016601:RNA-Binding Proteins; D013449:Sulfonamides; D025801:Ubiquitin; C494832:BIRC3 protein, human; D000075747:Baculoviral IAP Repeat-Containing 3 Protein; D044767:Ubiquitin-Protein Ligases; D053181:Caspase 8