Determination of cell survival by RING-mediated regulation of inhibitor of apoptosis (IAP) protein abundance

doi:10.1073/pnas.0502828102

Determination of cell survival by RING-mediated regulation of inhibitor of apoptosis (IAP) protein abundance

^*The Walter and Eliza Hall Institute of Medical Research, 1G Royal Parade, Parkville, Victoria 3050, Australia; ^‡Murdoch Childrens Research Institute, Flemington Road, Parkville, Victoria 3052, Australia; and ^§Biochemistry Department, University of Otago, Dunedin 9001, New Zealand

Edited by Tak Wah Mak, University of Toronto, Toronto, ON, Canada, and approved September 12, 2005 (received for review April 6, 2005)

Abstract

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.

Footnotes

↵ † To whom correspondence may be addressed. E-mail: silke{at}wehi.edu.au or vaux{at}wehi.edu.au.
Author contributions: J.S. and D.L.V. designed research; J.S., T.K., D.C., C.L.D., and M.P. performed research; J.S., P.G.E., and D.C.S.H. contributed new reagents/analytic tools; J.S. and D.L.V. analyzed data; and J.S. and D.L.V. wrote the paper.
Conflict of interest statement: No conflicts declared.
This paper was submitted directly (Track II) to the PNAS office.
Abbreviations: IAP, inhibitor of apoptosis; BIR, baculoviral IAP repeat; XIAP, X-linked IAP; cIAP, cellular IAP; TRAF, TNF receptor-associated factor.