Cytosolic Hsp60 Is Involved in the NF-κB-Dependent Survival of Cancer Cells via IKK Regulation
Open Access
- 23 March 2010
- journal article
- research article
- Published by Public Library of Science (PLoS) in PLOS ONE
- Vol. 5 (3), e9422
- https://doi.org/10.1371/journal.pone.0009422
Abstract
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-α-mediated activation of the IKK/NF-κB survival pathway via direct interaction with IKKα/β in the cytoplasm. Selective loss or blockade of cytosolic Hsp60 by specific antisense oligonucleotide or neutralizing antibody diminished the IKK/NF-κB activation and the expression of NF-κB target genes, such as Bfl-1/A1 and MnSOD, which thus augmented intracellular ROS production and ASK1-dependent cell death, in response to TNF-α. Conversely, the ectopic expression of cytosol-targeted Hsp60 enhanced IKK/NF-κB 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-κB pathway.Keywords
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