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PMID: 17652454 Published · ppublish English Journal Article Research Support, Non-U.S. Gov't

Disulfide Bond-mediated multimerization of Ask1 and its reduction by thioredoxin-1 regulate H(2)O(2)-induced c-Jun NH(2)-terminal kinase activation and apoptosis.

Molecular biology of the cell ·Vol. 18 ·No. 10 ·2007-10-00 ·Pages 3903-13

Nadeau PJ, Charette SJ, Toledano MB, Landry J

Abstract

Apoptosis signal-regulated kinase-1 (Ask1) lies upstream of a major redox-sensitive pathway leading to the activation of Jun NH(2)-terminal kinase (JNK) and the induction of apoptosis. We found that cell exposure to H(2)O(2) caused the rapid oxidation of Ask1, leading to its multimerization through the formation of interchain disulfide bonds. Oxidized Ask1 was fully reduced within minutes after induction by H(2)O(2). During this reduction, the thiol-disulfide oxidoreductase thioredoxin-1 (Trx1) became covalently associated with Ask1. Overexpression of Trx1 accelerated the reduction of Ask1, and a redox-inactive mutant of Trx1 (C35S) remained trapped with Ask1, blocking its reduction. Preventing the oxidation of Ask1 by either overexpressing Trx1 or using an Ask1 mutant in which the sensitive cysteines were mutated (Ask1-DeltaCys) impaired the activation of JNK and the induction of apoptosis while having little effect on Ask1 activation. These results indicate that Ask1 oxidation is required at a step subsequent to activation for signaling downstream of Ask1 after H(2)O(2) treatment.

MeSH Terms
Apoptosis/drug effects Cysteine/genetics Disulfides/metabolism Enzyme Activation/drug effects HeLa Cells Humans Hydrogen Peroxide/pharmacology JNK Mitogen-Activated Protein Kinases/metabolism MAP Kinase Kinase Kinase 5/chemistry,metabolism Models, Biological Mutation/genetics Oxidation-Reduction/drug effects Phosphorylation/drug effects Protein Structure, Quaternary Signal Transduction/drug effects Thioredoxins/metabolism
Chemicals
Disulfides TXN protein, human Thioredoxins Hydrogen Peroxide JNK Mitogen-Activated Protein Kinases MAP Kinase Kinase Kinase 5 MAP3K5 protein, human Cysteine
Authors & Affiliations
4 authors, click to expand affiliations / ORCID
Nadeau Philippe J
Centre de recherche en cancérologie de l'Université Laval, L'Hôtel-Dieu de Québec, Québec G1R 2J6, Canada.
Charette Steve J
Toledano Michel B
Landry Jacques
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Article Info
Journal
Molecular biology of the cell
Abbr.
Mol Biol Cell
ISSN
1059-1524
DOI
10.1091/mbc.e07-05-0491
Published
2007-10-00
Epub
2007-00-25
Pages
3903-13
Language
English
Region
United States
NLM ID
9201390
PMCID
PMC1995733
Subset
IM
External Links
PubMed source DOI: 10.1091/mbc.e07-05-0491 PMC Full Text View journal details
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