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PMID: 14685266 Published · ppublish English Journal Article Research Support, Non-U.S. Gov't Research Support, U.S. Gov't, P.H.S.

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

The EMBO journal ·Vol. 23 ·No. 1 ·2004-01-14 ·Pages 244-54

Burstein E, Ganesh L, Dick RD, van De Sluis B, Wilkinson JC, Klomp LW, Wijmenga C, Brewer GJ, Nabel GJ, Duckett CS

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 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.

MeSH Terms
Adaptor Proteins, Signal Transducing Antibodies, Monoclonal/metabolism Blotting, Western Carrier Proteins Caspases/analysis Cell Line Cell Survival Copper/metabolism Fluorescent Dyes Gene Expression Regulation Green Fluorescent Proteins HeLa Cells Homeostasis Humans Kidney/cytology Luminescent Proteins Microscopy, Confocal Models, Biological Point Mutation Precipitin Tests Protein Biosynthesis Proteins/genetics,metabolism RNA Interference RNA, Small Interfering/metabolism Recombinant Fusion Proteins/metabolism Two-Hybrid System Techniques Ubiquitin/genetics,metabolism X-Linked Inhibitor of Apoptosis Protein
Chemicals
Adaptor Proteins, Signal Transducing Antibodies, Monoclonal COMMD1 protein, human Carrier Proteins Fluorescent Dyes Luminescent Proteins Proteins RNA, Small Interfering Recombinant Fusion Proteins Ubiquitin X-Linked Inhibitor of Apoptosis Protein XIAP protein, human Green Fluorescent Proteins Copper Caspases
Authors & Affiliations
10 authors, click to expand affiliations / ORCID
Burstein Ezra
Department of Internal Medicine, University of Michigan Medical School, Ann Arbor, MI, USA.
Ganesh Lakshmanan
Dick Robert D
van De Sluis Bart
Wilkinson John C
Klomp Leo W J
Wijmenga Cisca
Brewer George J
Nabel Gary J
Duckett Colin S
References (48)
48 references, click to expand
  1. The serine protease Omi/HtrA2 regulates apoptosis by binding XIAP through a reaper-like motif.
    J Biol Chem. 2002 Jan 4;277(1):439-44 PMID: 11602612
  2. A serine protease, HtrA2, is released from the mitochondria and interacts with XIAP, inducing cell death.
    Mol Cell. 2001 Sep;8(3):613-21 PMID: 11583623
  3. Identification of a new copper metabolism gene by positional cloning in a purebred dog population.
    Hum Mol Genet. 2002 Jan 15;11(2):165-73 PMID: 11809725
  4. A conserved tetrapeptide motif: potentiating apoptosis through IAP-binding.
    Cell Death Differ. 2002 Feb;9(2):93-5 PMID: 11840157
  5. IAP suppression of apoptosis involves distinct mechanisms: the TAK1/JNK1 signaling cascade and caspase inhibition.
    Mol Cell Biol. 2002 Mar;22(6):1754-66 PMID: 11865055
  6. TNF-RII and c-IAP1 mediate ubiquitination and degradation of TRAF2.
    Nature. 2002 Mar 21;416(6878):345-7 PMID: 11907583
  7. The anti-apoptotic activity of XIAP is retained upon mutation of both the caspase 3- and caspase 9-interacting sites.
    J Cell Biol. 2002 Apr 1;157(1):115-24 PMID: 11927604
  8. Molecular mechanisms of copper uptake and distribution.
    Curr Opin Chem Biol. 2002 Apr;6(2):171-80 PMID: 12039001
  9. Cellular response to oxidative stress: signaling for suicide and survival.
    J Cell Physiol. 2002 Jul;192(1):1-15 PMID: 12115731
  10. XIAP inhibition of caspase-3 preserves its association with the Apaf-1 apoptosome and prevents CD95- and Bax-induced apoptosis.
    Cell Death Differ. 2002 Sep;9(9):881-92 PMID: 12181739
  11. Proteasome-mediated degradation of Smac during apoptosis: XIAP promotes Smac ubiquitination in vitro.
    J Biol Chem. 2002 Sep 27;277(39):36611-6 PMID: 12121969
  12. NF-kappaB as a primary regulator of the stress response.
    Oncogene. 1999 Nov 1;18(45):6163-71 PMID: 10557108
  13. A new internal-ribosome-entry-site motif potentiates XIAP-mediated cytoprotection.
    Nat Cell Biol. 1999 Jul;1(3):190-2 PMID: 10559907
  14. The role of multiubiquitination in dislocation and degradation of the alpha subunit of the T cell antigen receptor.
    J Biol Chem. 1999 Dec 24;274(52):36852-8 PMID: 10601236
  15. Recognition of the polyubiquitin proteolytic signal.
    EMBO J. 2000 Jan 4;19(1):94-102 PMID: 10619848
  16. Ubiquitin protein ligase activity of IAPs and their degradation in proteasomes in response to apoptotic stimuli.
    Science. 2000 May 5;288(5467):874-7 PMID: 10797013
  17. Activation of NF-kappa B by XIAP, the X chromosome-linked inhibitor of apoptosis, in endothelial cells involves TAK1.
    J Biol Chem. 2000 Jul 21;275(29):22064-8 PMID: 10807933
  18. Smac, a mitochondrial protein that promotes cytochrome c-dependent caspase activation by eliminating IAP inhibition.
    Cell. 2000 Jul 7;102(1):33-42 PMID: 10929711
  19. Identification of DIABLO, a mammalian protein that promotes apoptosis by binding to and antagonizing IAP proteins.
    Cell. 2000 Jul 7;102(1):43-53 PMID: 10929712
  20. Activation of the IkappaB kinase complex by TRAF6 requires a dimeric ubiquitin-conjugating enzyme complex and a unique polyubiquitin chain.
    Cell. 2000 Oct 13;103(2):351-61 PMID: 11057907
  21. Survivin and the inner centromere protein INCENP show similar cell-cycle localization and gene knockout phenotype.
    Curr Biol. 2000 Nov 2;10(21):1319-28 PMID: 11084331
  22. Structural basis for binding of Smac/DIABLO to the XIAP BIR3 domain.
    Nature. 2000 Dec 21-28;408(6815):1004-8 PMID: 11140637
  23. Structural basis of IAP recognition by Smac/DIABLO.
    Nature. 2000 Dec 21-28;408(6815):1008-12 PMID: 11140638
  24. xIAP induces cell-cycle arrest and activates nuclear factor-kappaB : new survival pathways disabled by caspase-mediated cleavage during apoptosis of human endothelial cells.
    Circ Res. 2001 Feb 16;88(3):282-90 PMID: 11179195
  25. A conserved XIAP-interaction motif in caspase-9 and Smac/DIABLO regulates caspase activity and apoptosis.
    Nature. 2001 Mar 1;410(6824):112-6 PMID: 11242052
  26. Structural basis of caspase-7 inhibition by XIAP.
    Cell. 2001 Mar 9;104(5):769-80 PMID: 11257230
  27. Structural basis of caspase inhibition by XIAP: differential roles of the linker versus the BIR domain.
    Cell. 2001 Mar 9;104(5):781-90 PMID: 11257231
  28. Structural basis for the inhibition of caspase-3 by XIAP.
    Cell. 2001 Mar 9;104(5):791-800 PMID: 11257232
  29. The molecular basis of copper-transport diseases.
    Trends Mol Med. 2001 Feb;7(2):64-9 PMID: 11286757
  30. Characterization of XIAP-deficient mice.
    Mol Cell Biol. 2001 May;21(10):3604-8 PMID: 11313486
  31. Molecular cloning of ILP-2, a novel member of the inhibitor of apoptosis protein family.
    Mol Cell Biol. 2001 Jul;21(13):4292-301 PMID: 11390657
  32. XIAP, the guardian angel.
    Nat Rev Mol Cell Biol. 2001 Jul;2(7):550-6 PMID: 11433370
  33. X-linked inhibitor of apoptosis protein functions as a cofactor in transforming growth factor-beta signaling.
    J Biol Chem. 2001 Jul 13;276(28):26542-9 PMID: 11356828
  34. Ubiquitin: not just for proteasomes anymore.
    Curr Opin Cell Biol. 2003 Apr;15(2):184-90 PMID: 12648674
  35. Omi/HtrA2 catalytic cleavage of inhibitor of apoptosis (IAP) irreversibly inactivates IAPs and facilitates caspase activity in apoptosis.
    Genes Dev. 2003 Jun 15;17(12):1487-96 PMID: 12815069
  36. Inhibitor of apoptosis proteins are substrates for the mitochondrial serine protease Omi/HtrA2.
    J Biol Chem. 2003 Aug 22;278(34):31469-72 PMID: 12835328
  37. The copper toxicosis gene product Murr1 directly interacts with the Wilson disease protein.
    J Biol Chem. 2003 Oct 24;278(43):41593-6 PMID: 12968035
  38. The ubiquitously expressed MURR1 protein is absent in canine copper toxicosis.
    J Hepatol. 2003 Nov;39(5):703-9 PMID: 14568250
  39. A novel genetic system to detect protein-protein interactions.
    Nature. 1989 Jul 20;340(6230):245-6 PMID: 2547163
  40. An apoptosis-inhibiting baculovirus gene with a zinc finger-like motif.
    J Virol. 1993 Apr;67(4):2168-74 PMID: 8445726
  41. The TNFR2-TRAF signaling complex contains two novel proteins related to baculoviral inhibitor of apoptosis proteins.
    Cell. 1995 Dec 29;83(7):1243-52 PMID: 8548810
  42. Induction of nuclear factor kappaB by the CD30 receptor is mediated by TRAF1 and TRAF2.
    Mol Cell Biol. 1997 Mar;17(3):1535-42 PMID: 9032281
  43. X-linked IAP is a direct inhibitor of cell-death proteases.
    Nature. 1997 Jul 17;388(6639):300-4 PMID: 9230442
  44. Human IAP-like protein regulates programmed cell death downstream of Bcl-xL and cytochrome c.
    Mol Cell Biol. 1998 Jan;18(1):608-15 PMID: 9418907
  45. Selective activation of JNK1 is necessary for the anti-apoptotic activity of hILP.
    Proc Natl Acad Sci U S A. 1998 May 26;95(11):6015-20 PMID: 9600909
  46. XIAP, a cellular member of the inhibitor of apoptosis protein family, links the receptors to TAB1-TAK1 in the BMP signaling pathway.
    EMBO J. 1999 Jan 4;18(1):179-87 PMID: 9878061
  47. Ubiquitin-protein ligase activity of X-linked inhibitor of apoptosis protein promotes proteasomal degradation of caspase-3 and enhances its anti-apoptotic effect in Fas-induced cell death.
    Proc Natl Acad Sci U S A. 2001 Jul 17;98(15):8662-7 PMID: 11447297
  48. Identification of Omi/HtrA2 as a mitochondrial apoptotic serine protease that disrupts inhibitor of apoptosis protein-caspase interaction.
    J Biol Chem. 2002 Jan 4;277(1):432-8 PMID: 11606597
Article Info
Journal
The EMBO journal
Abbr.
EMBO J
ISSN
0261-4189
DOI
10.1038/sj.emboj.7600031
Published
2004-01-14
Epub
2003-00-18
Pages
244-54
Language
English
Region
England
NLM ID
8208664
PMCID
PMC1271669
Subset
IM
Grants
NIDDK NIH HHS · P30 DK034933 · United States
NCI NIH HHS · T32 CA009676 · United States
NIDDK NIH HHS · 5P30 DK34933-18 · United States
NCI NIH HHS · T32 CA09676 · United States
External Links
PubMed source DOI: 10.1038/sj.emboj.7600031 PMC Full Text View journal details
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