Cytosolic Hsp60 Is Involved in the NF-kB-Dependent Survival of Cancer Cells via IKK Regulation

Jung Nyeo Chun, Boae Choi, Kyung Wha Lee, Doo Jae Lee, Dong Hoon Kang, Joo Young Lee, In Sung Song, Hye In Kim, Sang Hee Lee, Hyeon Soo Kim, Na Kyung Lee, Soo Young Lee, Kong Joo Lee, Jaesang Kim, Sang Won Kang

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64 Citations (Scopus)

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-kB survival pathway via direct interaction with IKKa/b in the cytoplasm. Selective loss or blockade of cytosolic Hsp60 by specific antisense oligonucleotide or neutralizing antibody diminished the IKK/NF-kB activation and the expression of NF-kB 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-kB 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-kB pathway.

Original languageEnglish
Article numbere9422
JournalPloS one
Volume5
Issue number3
DOIs
Publication statusPublished - 2010

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)
  • Agricultural and Biological Sciences(all)
  • General

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    Chun, J. N., Choi, B., Lee, K. W., Lee, D. J., Kang, D. H., Lee, J. Y., Song, I. S., Kim, H. I., Lee, S. H., Kim, H. S., Lee, N. K., Lee, S. Y., Lee, K. J., Kim, J., & Kang, S. W. (2010). Cytosolic Hsp60 Is Involved in the NF-kB-Dependent Survival of Cancer Cells via IKK Regulation. PloS one, 5(3), [e9422]. https://doi.org/10.1371/journal.pone.0009422