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.
Highlights
Mammalian cells express a number of survival genes that play the roles in inhibiting caspase activation, removing harmful oxygen radicals, defending mitochondrial function, and checking cell cycle
heat shock protein 60 (Hsp60) interacts with IKK complex in cytoplasm To identify an additional component, we examined the molecular composition of the latent IKK complex using a proteomic technique combining immuno-affinity purification and mass spectrometry
The present study demonstrates that the cytosolic Hsp60 interacts with the IKK complex and enhances its activation
Summary
Mammalian cells express a number of survival genes that play the roles in inhibiting caspase activation, removing harmful oxygen radicals, defending mitochondrial function, and checking cell cycle. The NF-kB-dependent survival genes include antiapoptotic genes, such as c-IAPs and c-FLIP, and mitochondrial safeguard genes, such as manganese-superoxide dismutase (MnSOD) and Bcl-2 family members [2,3,4]. A central kinase in NF-kB activation pathway is the inhibitor of kB kinase (IkB kinase or IKK) that phosphorylates the IkB protein in two aminoterminal serine residues, leading to its ubiquitinylation and proteosomal degradation and to the consequent liberation of NF-kB proteins [5]. Numerous efforts have been made to delineate the regulation of IKK activation. The phosphorylation-dependent regulation of IKK activation has been characterized [7].
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