A novel role for XIAP in copper homeostasis through regulation of MURR1.
XIAP is a potent suppressor of apoptosis that directly inhibits specific members of the caspase family of cysteine proteases. Here we demonstrate a novel role for XIAP in the control of intracellular copper levels. XIAP was found to interact with MURR1, a factor recently implicated in copper homeostasis. XIAP binds to MURR1 in a manner that is distinct from that utilized by XIAP to bind caspases, and consistent with this, MURR1 did not affect the antiapoptotic properties of XIAP. However, cells and tissues derived from Xiap-deficient mice were found to contain reduced copper levels, while suppression of MURR1 resulted in increased intracellular copper in cultured cells. Consistent with these opposing effects, XIAP was observed to negatively regulate MURR1 protein levels by the formation of K48 polyubiquitin chains on MURR1 that promote its degradation. These findings represent the first described phenotypic alteration in Xiap-deficient mice and demonstrate that XIAP can function through MURR1 to regulate copper homeostasis.
Burstein
Ezra
E
Department of Internal Medicine, University of Michigan Medical School, Ann Arbor, MI, USA.
Ganesh
Lakshmanan
L
Dick
Robert D
RD
van De Sluis
Bart
B
Wilkinson
John C
JC
Klomp
Leo W J
LW
Wijmenga
Cisca
C
Brewer
George J
GJ
Nabel
Gary J
GJ
Duckett
Colin S
CS
D048868:Adaptor Proteins, Signal Transducing; D000911:Antibodies, Monoclonal / Q000378:metabolism; D015153:Blotting, Western; D002352:Carrier Proteins; D020169:Caspases / Q000032:analysis; D002460:Cell Line; D002470:Cell Survival; D003300:Copper / Q000378:metabolism*; D005456:Fluorescent Dyes; D005786:Gene Expression Regulation; D049452:Green Fluorescent Proteins; D006367:HeLa Cells; D006706:Homeostasis; D006801:Humans; D007668:Kidney / Q000166:cytology*; D008164:Luminescent Proteins; D018613:Microscopy, Confocal; D008954:Models, Biological; D017354:Point Mutation; D011233:Precipitin Tests; D014176:Protein Biosynthesis; D011506:Proteins / Q000235:genetics / Q000378:metabolism*; D034622:RNA Interference; D034741:RNA, Small Interfering / Q000378:metabolism; D011993:Recombinant Fusion Proteins / Q000378:metabolism; D020798:Two-Hybrid System Techniques; D025801:Ubiquitin / Q000235:genetics / Q000378:metabolism; D051636:X-Linked Inhibitor of Apoptosis Protein
D048868:Adaptor Proteins, Signal Transducing; D000911:Antibodies, Monoclonal; C480519:COMMD1 protein, human; D002352:Carrier Proteins; D005456:Fluorescent Dyes; D008164:Luminescent Proteins; D011506:Proteins; D034741:RNA, Small Interfering; D011993:Recombinant Fusion Proteins; D025801:Ubiquitin; D051636:X-Linked Inhibitor of Apoptosis Protein; C496866:XIAP protein, human; D049452:Green Fluorescent Proteins; D003300:Copper; D020169:Caspases