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Stress-induced nuclear import of apoptosis signal-regulating kinase 1 is mediated by karyopherin α2/β1 heterodimer.
- Source :
-
Biochimica et biophysica acta [Biochim Biophys Acta] 2013 Mar; Vol. 1833 (3), pp. 583-92. Date of Electronic Publication: 2012 Oct 31. - Publication Year :
- 2013
-
Abstract
- The apoptosis signal-regulating kinase 1 (ASK1) is activated in response to a wide variety of extracellular stressors. Consequently, dysregulation of ASK1 is associated with multiple pathologies. Here, we show that ASK1 translocates from the cytoplasm to the nucleus in HEK293 cells and human cardiomyocytes in response to hydrogen peroxide (H(2)O(2)) or angiotensin respectively. Immunoprecipitation and mass spectrometry experiments reveal that ASK1 physically interacts with the karyopherin α2/β1 heterodimer in response to stress and genetic knockdown experiments confirm that this association mediates H(2)O(2)-induced ASK1 nuclear translocation. In addition, we have identified a nuclear localization signal (NLS)-like motif within the primary amino acid sequence of ASK1 composed of two clusters of basic amino acids separated by an intervening 16 amino acid spacer, KR[ACANDLLVDEFLKVSS]KKKK. Mutation of the downstream lysine cluster markedly reduces the H(2)O(2)-induced ASK1-karyopherin α2/β1 interaction and inhibits ASK1 nuclear translocation. Furthermore, we demonstrate that nuclear ASK1 is active and participates in H(2)O(2)-induced ASK1-mediated cell death. Collectively, our findings have identified a functional interaction between ASK1 and the karyopherin α2/β1 heterodimer and have also revealed a novel mechanism by which nuclear trafficking regulates the apoptotic function of ASK1 in response to stress.<br /> (Copyright © 2012 Elsevier B.V. All rights reserved.)
- Subjects :
- Amino Acid Sequence
Angiotensins pharmacology
Blotting, Western
Cell Nucleus metabolism
Cell Proliferation
Cells, Cultured
Cytoplasm metabolism
Fluorescent Antibody Technique
Humans
Immunoprecipitation
Kidney cytology
Kidney drug effects
Kidney metabolism
MAP Kinase Kinase Kinase 5 genetics
Molecular Sequence Data
Mutation genetics
Myocytes, Cardiac cytology
Myocytes, Cardiac metabolism
Nuclear Localization Signals drug effects
Oxidants pharmacology
Protein Binding
Protein Multimerization
Sequence Homology, Amino Acid
Signal Transduction drug effects
alpha Karyopherins genetics
beta Karyopherins genetics
Apoptosis drug effects
Hydrogen Peroxide pharmacology
MAP Kinase Kinase Kinase 5 metabolism
Myocytes, Cardiac drug effects
Oxidative Stress drug effects
alpha Karyopherins metabolism
beta Karyopherins metabolism
Subjects
Details
- Language :
- English
- ISSN :
- 0006-3002
- Volume :
- 1833
- Issue :
- 3
- Database :
- MEDLINE
- Journal :
- Biochimica et biophysica acta
- Publication Type :
- Academic Journal
- Accession number :
- 23123190
- Full Text :
- https://doi.org/10.1016/j.bbamcr.2012.10.023