Regulation of the copper chaperone CCS by XIAP-mediated ubiquitination.
In order to balance the cellular requirements for copper with its toxic properties, an elegant set of mechanisms has evolved to regulate and buffer intracellular copper. The X-linked inhibitor of apoptosis (XIAP) protein was recently identified as a copper-binding protein and regulator of copper homeostasis, although the mechanism by which XIAP binds copper in the cytosol is unclear. Here we describe the identification of the copper chaperone for superoxide dismutase (CCS) as a mediator of copper delivery to XIAP in cells. We also find that CCS is a target of the E3 ubiquitin ligase activity of XIAP, although interestingly, ubiquitination of CCS by XIAP was found to lead to enhancement of its chaperone activity toward its physiologic target, superoxide dismutase 1, rather than proteasomal degradation. Collectively, our results reveal novel links among apoptosis, copper metabolism, and redox regulation through the XIAP-CCS complex.
Department of Pathology, University of Michigan Medical School, Ann Arbor, Michigan 48109, USA.
Graham F
GF
Brady
Stefanie
S
Galbán
Xuwen
X
Liu
Venkatesha
V
Basrur
Jonathan D
JD
Gitlin
Kojo S J
KS
Elenitoba-Johnson
Thomas E
TE
Wilson
Colin S
CS
Duckett
D000818:Animals; D002460:Cell Line; D003300:Copper / Q000378:metabolism*; D004789:Enzyme Activation; D006801:Humans; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D018832:Molecular Chaperones / Q000235:genetics / Q000378:metabolism*; D029701:Saccharomyces cerevisiae Proteins / Q000235:genetics / Q000378:metabolism*; D013482:Superoxide Dismutase / Q000235:genetics / Q000378:metabolism; D000072105:Superoxide Dismutase-1; D014018:Tissue Distribution; D054875:Ubiquitination; D051636:X-Linked Inhibitor of Apoptosis Protein / Q000235:genetics / Q000378:metabolism*
C114678:CCS protein, human; C491960:CCS1 protein, S cerevisiae; D018832:Molecular Chaperones; C000606290:SOD1 protein, human; D029701:Saccharomyces cerevisiae Proteins; D051636:X-Linked Inhibitor of Apoptosis Protein; D003300:Copper; C000606291:Sod1 protein, mouse; D013482:Superoxide Dismutase; D000072105:Superoxide Dismutase-1