Enhanced interaction between Hsp90 and raptor regulates mTOR signaling upon T cell activation.
The mammalian target of rapamycin (mTOR) is an evolutionarily conserved kinase which plays a role in integrating environmental cues. mTOR signals via two complexes: TORC1, which contains the Regulatory Associated Protein of TOR (raptor), and TORC2, which contains the Rapamycin-insensitive Companion of TOR (rictor). The immunosuppressive/anti-cancer agent rapamycin inhibits TORC1 function by disrupting the mTOR-raptor interaction. In an effort to understand the downstream consequences of TORC1 activation in T cells we performed a proteomic analysis of raptor binding proteins. Using this approach we have identified Hsp90 as an activation-induced binding partner of raptor in T cells. Pharmacologic inhibition of Hsp90 leads to a decrease in raptor expression and TORC1 activity. Furthermore, full T cell activation during Hsp90 blockade leads to T cell tolerance in the form of anergy. Overall, our findings suggest that Hsp90 inhibitors might represent a novel means of promoting T cell tolerance.
Delgoffe
Greg M
GM
Sidney-Kimmel Comprehensive Cancer Research Center, Johns Hopkins University School of Medicine, Baltimore, MD 21231, United States.
Kole
Thomas P
TP
Cotter
Robert J
RJ
Powell
Jonathan D
JD
D048868:Adaptor Proteins, Signal Transducing; D000818:Animals; D002352:Carrier Proteins / Q000378:metabolism*; D002851:Chromatography, High Pressure Liquid; D004591:Electrophoresis, Polyacrylamide Gel; D018841:HSP90 Heat-Shock Proteins / Q000378:metabolism*; D015151:Immunoblotting; D007166:Immunosuppressive Agents / Q000494:pharmacology; D008213:Lymphocyte Activation / Q000187:drug effects; D013058:Mass Spectrometry; D051379:Mice; D011485:Protein Binding; D011494:Protein Kinases / Q000378:metabolism*; D020543:Proteome / Q000302:isolation & purification / Q000378:metabolism; D040901:Proteomics / Q000379:methods; D000076223:Regulatory-Associated Protein of mTOR; D015398:Signal Transduction; D020123:Sirolimus / Q000494:pharmacology; D013601:T-Lymphocytes / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D058570:TOR Serine-Threonine Kinases; D014157:Transcription Factors / Q000378:metabolism
D048868:Adaptor Proteins, Signal Transducing; D002352:Carrier Proteins; C519509:Crtc1 protein, mouse; D018841:HSP90 Heat-Shock Proteins; D007166:Immunosuppressive Agents; D020543:Proteome; D000076223:Regulatory-Associated Protein of mTOR; C540162:Rptor protein, mouse; D014157:Transcription Factors; D011494:Protein Kinases; C546843:mTOR protein, mouse; D058570:TOR Serine-Threonine Kinases; D020123:Sirolimus