Signal responsiveness of IkappaB kinases is determined by Cdc37-assisted transient interaction with Hsp90.
The IkappaB kinase (IKK) holocomplex, containing the kinases IKKalpha, IKKbeta, and the scaffold NEMO (NF-kappaB essential modifier), mediates activation of NF-kappaB by numerous physiological stimuli. Heat shock protein 90 (Hsp90) and the co-chaperone Cdc37 have been indicated as additional subunits, but their specific functions in signal transduction are indistinct. Using an RNA interference approach, we demonstrate that Cdc37 recruits Hsp90 to the IKK complex in a transitory manner, preferentially via IKKalpha. Binding is conferred by N-terminal as well as C-terminal residues of Cdc37. Cdc37 is essential for the maturation of de novo synthesized IKKs into enzymatically competent kinases but not for assembly of an IKK holocomplex. Mature IKKs, T-loop-phosphorylated after stimulation either by receptor-mediated signaling or upon DNA damage, further require Hsp90-Cdc37 to generate an activated state. Thus, the present data denote Hsp90-Cdc37 as a transiently acting essential regulatory component of IKK signaling.
Hinz
Michael
M
Max Delbrück Center for Molecular Medicine, Robert-Rössle-Strasse 10, 13125 Berlin, Germany.
Broemer
Meike
M
Arslan
Seda Cöl
SC
Otto
Albrecht
A
Mueller
Eva-Christina
EC
Dettmer
Rudolf
R
Scheidereit
Claus
C
D018797:Cell Cycle Proteins / Q000378:metabolism*; D002460:Cell Line; D018833:Chaperonins / Q000378:metabolism*; D018841:HSP90 Heat-Shock Proteins / Q000378:metabolism*; D006367:HeLa Cells; D006801:Humans; D051550:I-kappa B Kinase / Q000378:metabolism*; D015398:Signal Transduction; D022021:Tacrolimus Binding Proteins / Q000378:metabolism; D000099159:Tacrolimus Binding Protein 5
D018797:Cell Cycle Proteins; D018833:Chaperonins; D018841:HSP90 Heat-Shock Proteins; D051550:I-kappa B Kinase; D022021:Tacrolimus Binding Proteins; D000099159:Tacrolimus Binding Protein 5; C498362:CDC37 protein, human