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

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 IkappaB kinase gamma (IKKgamma) to inhibit IKK activity and consequently inhibit NF-kappaB-dependent antiapoptotic gene induction. An IKKgamma mutant, which interacts with Hsp70, competitively inhibits the Hsp70-IKKgamma interaction and relieves heat-mediated NF-kappaB 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-kappaB signaling. These results provide significant novel insights into the molecular mechanism for the pro-apoptotic behavior of Hsp70 in death-receptor-mediated cell death.