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Nondegradative ubiquitination of apoptosis inducing factor (AIF) by X-linked inhibitor of apoptosis at a residue critical for AIF-mediated chromatin degradation.
- Source :
-
Biochemistry [Biochemistry] 2011 Dec 27; Vol. 50 (51), pp. 11084-96. Date of Electronic Publication: 2011 Dec 02. - Publication Year :
- 2011
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Abstract
- Apoptosis inducing factor (AIF) is a mediator of caspase-independent cell death that is also necessary for mitochondrial energy production. How these seemingly opposite cellular functions of AIF are controlled is poorly understood. X-linked inhibitor of apoptosis (XIAP) is an endogenous inhibitor of caspases that also regulates several caspase-independent signaling pathways. The RING domain of XIAP possesses E3 ubiquitin ligase activity, though the importance of this function to signal regulation remains incompletely defined. XIAP binds and ubiquitinates AIF, and in this study, we determined the functional consequences of XIAP-mediated AIF ubiquitination. Unlike canonical ubiquitination, XIAP-dependent AIF ubiquitination did not lead to proteasomal degradation of AIF. Experiments using ubiquitin mutants demonstrated that the XIAP-dependent ubiquitin linkage was not formed through the commonly used lysine 48, suggesting a noncanonical ubiquitin linkage is employed. Further studies demonstrated that only lysine 255 of AIF was a target of XIAP-dependent ubiquitination. Using recombinant AIF, we determined that mutating lysine 255 of AIF interferes with the ability of AIF not only to bind DNA but also to degrade chromatin in vitro. These data indicate that XIAP regulates the death-inducing activity of AIF through nondegradative ubiquitination, further defining the role of XIAP in controlling AIF and caspase-independent cell death pathways.
- Subjects :
- Amino Acid Substitution
Apoptosis Inducing Factor chemistry
Apoptosis Inducing Factor genetics
Binding Sites
Cell Nucleus chemistry
Cell Nucleus metabolism
Cell Survival
Chromatin chemistry
DNA-Binding Proteins chemistry
DNA-Binding Proteins genetics
DNA-Binding Proteins metabolism
HEK293 Cells
HeLa Cells
Humans
Mutant Proteins chemistry
Mutant Proteins metabolism
NAD metabolism
Oxidation-Reduction
Peptide Fragments chemistry
Peptide Fragments genetics
Peptide Fragments metabolism
RING Finger Domains
Recombinant Proteins chemistry
Recombinant Proteins metabolism
Ubiquitin-Protein Ligases chemistry
Ubiquitin-Protein Ligases metabolism
X-Linked Inhibitor of Apoptosis Protein chemistry
Apoptosis Inducing Factor metabolism
Chromatin metabolism
Lysine metabolism
Ubiquitination
X-Linked Inhibitor of Apoptosis Protein metabolism
Subjects
Details
- Language :
- English
- ISSN :
- 1520-4995
- Volume :
- 50
- Issue :
- 51
- Database :
- MEDLINE
- Journal :
- Biochemistry
- Publication Type :
- Academic Journal
- Accession number :
- 22103349
- Full Text :
- https://doi.org/10.1021/bi201483g