Determination of cell survival by RING-mediated regulation of inhibitor of apoptosis (IAP) protein abundance.
Inhibitor of apoptosis (IAP) proteins, which bind to caspases via their baculoviral IAP repeat domains, also bear RING domains that enable them to promote ubiquitylation of themselves and other interacting proteins. Here we show that the RING domain of cIAP1 allows it to bind directly to the RING of X-linked IAP, causing its ubiquitylation and degradation by the proteasome, thus revealing a mechanism by which IAPs can regulate their abundance. Expression of a construct containing the RING of cellular IAP1 was able to deplete melanoma cells of endogenous X-linked IAP, promoted apoptosis, and also markedly reduced their clonogenicity when treated with cisplatin. Cross control of protein levels by RING domains may therefore enable their levels to be manipulated therapeutically.
Silke
John
J
The Walter and Eliza Hall Institute of Medical Research, 1G Royal Parade, Parkville, Victoria 3050, Australia. silke@wehi.edu.au
Kratina
Tobias
T
Chu
Diep
D
Ekert
Paul G
PG
Day
Catherine L
CL
Pakusch
Miha
M
Huang
David C S
DC
Vaux
David L
DL
D000595:Amino Acid Sequence; D017209:Apoptosis; D020169:Caspases / Q000502:physiology; D002460:Cell Line; D002470:Cell Survival; D002945:Cisplatin / Q000627:therapeutic use; D006706:Homeostasis; D051034:Inhibitor of Apoptosis Proteins / Q000378:metabolism*; D008545:Melanoma / Q000188:drug therapy / Q000473:pathology; D008969:Molecular Sequence Data; D046988:Proteasome Endopeptidase Complex / Q000502:physiology; D017434:Protein Structure, Tertiary; D044767:Ubiquitin-Protein Ligases / Q000502:physiology*; D051636:X-Linked Inhibitor of Apoptosis Protein / Q000378:metabolism*
D051034:Inhibitor of Apoptosis Proteins; D051636:X-Linked Inhibitor of Apoptosis Protein; D044767:Ubiquitin-Protein Ligases; D020169:Caspases; D046988:Proteasome Endopeptidase Complex; D002945:Cisplatin