期刊
PLOS ONE
卷 5, 期 3, 页码 -出版社
PUBLIC LIBRARY SCIENCE
DOI: 10.1371/journal.pone.0009422
关键词
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资金
- Ministry of Education, Science Technology
- KOSEF [R15-2006-020]
- National R&D Program for Cancer Control, Ministry of Health Welfare [0420190]
- Korea Ministry of Education, Science Technology
- Korea Health Promotion Institute [0420190] Funding Source: Korea Institute of Science & Technology Information (KISTI), National Science & Technology Information Service (NTIS)
Cytoplasmic presence of Hsp60, which is principally a nuclear gene-encoded mitochondrial chaperonin, has frequently been stated, but its role in intracellular signaling is largely unknown. In this study, we demonstrate that the cytosolic Hsp60 promotes the TNF-alpha-mediated activation of the IKK/NF-kappa B survival pathway via direct interaction with IKK alpha/beta in the cytoplasm. Selective loss or blockade of cytosolic Hsp60 by specific antisense oligonucleotide or neutralizing antibody diminished the IKK/NF-kappa B activation and the expression of NF-kappa B target genes, such as Bfl-1/A1 and MnSOD, which thus augmented intracellular ROS production and ASK1-dependent cell death, in response to TNF-alpha. Conversely, the ectopic expression of cytosol-targeted Hsp60 enhanced IKK/NF-kappa B activation. Mechanistically, the cytosolic Hsp60 enhanced IKK activation via upregulating the activation-dependent serine phosphorylation in a chaperone-independent manner. Furthermore, transgenic mouse study showed that the cytosolic Hsp60 suppressed hepatic cell death induced by diethylnitrosamine in vivo. The cytosolic Hsp60 is likely to be a regulatory component of IKK complex and it implicates the first mitochondrial factor that regulates cell survival via NF-kappa B pathway.
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