Journal
BIOCHIMICA ET BIOPHYSICA ACTA-MOLECULAR CELL RESEARCH
Volume 1833, Issue 3, Pages 583-592Publisher
ELSEVIER SCIENCE BV
DOI: 10.1016/j.bbamcr.2012.10.023
Keywords
Apoptosis signal-regulated kinase 1; Karyopherin alpha 2/beta 1; Nuclear localization signal; Nuclear translocation
Categories
Ask authors/readers for more resources
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 (H2O2) or angiotensin respectively. Immunoprecipitation and mass spectrometry experiments reveal that ASK1 physically interacts with the karyopherin alpha 2/beta 1 heterodimer in response to stress and genetic knockdown experiments confirm that this association mediates H2O2-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 H2O2-induced ASK1-karyopherin alpha 2/beta 1 interaction and inhibits ASK1 nuclear translocation. Furthermore, we demonstrate that nuclear ASK1 is active and participates in H2O2-induced ASK1-mediated cell death. Collectively, our findings have identified a functional interaction between ASK1 and the karyopherin alpha 2/beta 1 heterodimer and have also revealed a novel mechanism by which nuclear trafficking regulates the apoptotic function of ASK1 in response to stress. (C) 2012 Elsevier B.V. All rights reserved.
Authors
I am an author on this paper
Click your name to claim this paper and add it to your profile.
Reviews
Recommended
No Data Available