Cytosolic Hsp60 is involved in the NF-kappaB-dependent survival of cancer cells via IKK regulation.
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.
Chun
Jung Nyeo
JN
Division of Life and Pharmaceutical Science and Center for Cell Signaling and Drug Discovery Research, Ewha Womans University, Seoul, Korea.
Choi
Boae
B
Lee
Kyung Wha
KW
Lee
Doo Jae
DJ
Kang
Dong Hoon
DH
Lee
Joo Young
JY
Song
In Sung
IS
Kim
Hye In
HI
Lee
Sang-Hee
SH
Kim
Hyeon Soo
HS
Lee
Na Kyung
NK
Lee
Soo Young
SY
Lee
Kong-Joo
KJ
Kim
Jaesang
J
Kang
Sang Won
SW
D000818:Animals; D002470:Cell Survival; D018834:Chaperonin 60 / Q000378:metabolism*; D003593:Cytoplasm / Q000378:metabolism; D003600:Cytosol / Q000378:metabolism*; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D051550:I-kappa B Kinase / Q000378:metabolism*; D008297:Male; D051379:Mice; D016328:NF-kappa B / Q000378:metabolism*; D009369:Neoplasms / Q000473:pathology*; D016376:Oligonucleotides, Antisense / Q000235:genetics; D013482:Superoxide Dismutase / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism
D018834:Chaperonin 60; D016328:NF-kappa B; D016376:Oligonucleotides, Antisense; D014409:Tumor Necrosis Factor-alpha; D013482:Superoxide Dismutase; D051550:I-kappa B Kinase