A novel role for XIAP in copper homeostasis through regulation of MURR1

Ezra Burstein, Lakshmanan Ganesh, Robert D. Dick, Bart Van De Sluis, John C. Wilkinson, Leo W J Klomp, Cisca Wijmenga, George J. Brewer, Gary J. Nabel, Colin S. Duckett

Research output: Contribution to journalArticle

165 Scopus citations

Abstract

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 anti-apoptotic 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.

Original languageEnglish (US)
Pages (from-to)244-254
Number of pages11
JournalEMBO Journal
Volume23
Issue number1
DOIs
StatePublished - Jan 14 2004

Keywords

  • Copper
  • MURR1
  • Ubiquitin
  • XIAP

ASJC Scopus subject areas

  • Neuroscience(all)
  • Molecular Biology
  • Biochemistry, Genetics and Molecular Biology(all)
  • Immunology and Microbiology(all)

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  • Cite this

    Burstein, E., Ganesh, L., Dick, R. D., Van De Sluis, B., Wilkinson, J. C., Klomp, L. W. J., Wijmenga, C., Brewer, G. J., Nabel, G. J., & Duckett, C. S. (2004). A novel role for XIAP in copper homeostasis through regulation of MURR1. EMBO Journal, 23(1), 244-254. https://doi.org/10.1038/sj.emboj.7600031