Heat shock protein 90α recruits FLIPS to the death-inducing signaling complex and contributes to TRAIL resistance in human glioma

Heat shock protein 90(HSP90) is a molecular chaperone that contributes to the proper folding and stability of target proteins. Because HSP90 has been suggested to interact with FLIPS, the key regulator of tumor necrosis factor-alpha-related apoptosis-inducing ligand (TRAIL)-induced apoptosis in glioma cells, we examined the role HSP90 alpha played in controlling TRAIL response. HSP90 alpha was found to associate wit FLIPS in resting cells in a manner dependent on the ATP-binding NH2-terminal domain of HSP90 alpha. Following TRAIL exposure, HSP90 alpha. and the client FLIPS protein were recruited to the death-inducing signaling complex (DISC). Short interfering RNA-mediated suppression of HSP90 alpha did not alter the total cellular levels of FLIPs, but rather inhibited the recruitment of FLIPS and other antiapoptotic proteins such as RIP and FLIPL to the DISC, and sensitized otherwise resistant glioma cells to TRAIL-induced apoptosis. These results show that HSP90 alpha, by localizing FLIPS to the DISC, plays a key role in the resistance of tumor cells to TRAIL, and perhaps other proapoptotic agents. The results also define a novel means of apoptotic control by a HSP90 alpha that may in turn help explain the global antiapoptotic effects of this protein.