Hsp70 promotes TNF-mediated apoptosis by binding IKKγ and impairing NF-κB survival signaling

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Abstract
The major heat shock protein, Hsp70, can protect against cell death by directly interfering with mitochondrial apoptosis pathways. However, Hsp70 also sensitizes cells to certain apoptotic stimuli like TNF. Little is known about how Hsp70 enhances apoptosis. We demonstrate here that Hsp70 promotes TNF killing by specifically binding the coiled-coil domain of IκB kinase γ (IKKγ) to inhibit IKK activity and consequently inhibit NF-κB-dependent antiapoptotic gene induction. An IKKγ mutant, which interacts with Hsp70, competitively inhibits the Hsp70–IKKγ interaction and relieves heat-mediated NF-κB suppression. Depletion of Hsp70 expression with RNA interference rescues TNF-mediated cell death. Although TNF may or may not be sufficient to trigger apoptosis on its own, TNF-triggered apoptosis was initiated or made worse when Hsp70 expression increased to high levels to disrupt NF-κB signaling. These results provide significant novel insights into the molecular mechanism for the pro-apoptotic behavior of Hsp70 in death-receptor-mediated cell death.