Cytosolic Hsp60 is involved in the NF-kappaB-dependent survival of cancer cells via IKK regulation

• Published in: PloS one Vol. 5; no. 3; p. e9422
• Main Authors: Chun, Jung Nyeo, Choi, Boae, Lee, Kyung Wha, Lee, Doo Jae, Kang, Dong Hoon, Lee, Joo Young, Song, In Sung, Kim, Hye In, Lee, Sang-Hee, Kim, Hyeon Soo, Lee, Na Kyung, Lee, Soo Young, Lee, Kong-Joo, Kim, Jaesang, Kang, Sang Won
• Format: Journal Article
• Language: English
• Published: United States Public Library of Science (PLoS) 23.03.2010
• Subjects: Animals; Cell Survival; Chaperonin 60 - metabolism; Cytoplasm - metabolism; Cytosol - metabolism; Gene Expression Regulation, Neoplastic; Humans; I-kappa B Kinase - metabolism; Male; Mice; Neoplasms - pathology; NF-kappa B - metabolism; Oligonucleotides, Antisense - genetics; Superoxide Dismutase - metabolism; Tumor Necrosis Factor-alpha - metabolism
• ISSN: 1932-6203
• DOI: 10.1371/journal.pone.0009422

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