Requirement of Hsp90 activity for IκB kinase (IKK) biosynthesis and for constitutive and inducible IKK and NF-κB activation

被引:189
作者
Broemer, M
Krappmann, D
Scheidereit, C
机构
[1] Max Delbruck Ctr Mol Med, D-13092 Berlin, Germany
[2] Free Univ Berlin, Fac Biol Chem & Pharm, D-14195 Berlin, Germany
关键词
ubiquitin; chaperones; proteasome; ribosome; Reed-Sternberg cells; tumor cell pharmacology;
D O I
10.1038/sj.onc.1207705
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
The molecular chaperone Hsp90 affects the function and fate of a number of signaling molecules. We have investigated the Hsp90 requirement for constitutive and inducible activity of the IkappaB kinase (IKK) complex and of NF-kappaB. Inhibition by the Hsp90 ATPase inhibitors, geldanamycin (GA) and radicicol ( RC), revealed that Hsp90 controls IKKs at two levels, inducibility of enzymatic activity and biogenesis, which can be discriminated by short- and long-time GA incubation, respectively. Short-time inhibition of Hsp90 resulted in impaired IKK kinase activation by TNFalpha, IL-1beta or phorbolester PMA. Furthermore, GA inhibited constitutive activation of IKK and NF-kappaB in Hodgkin's lymphoma cells. Hsp90 function was also required for trans- and autophosphorylation of transfected IKKbeta. GA exposure for several hours resulted in a downmodulation of IKK complex alpha, beta and gamma subunits to various extent. Proteasome inhibition interfered with GA mediated IKK depletion and Hsp90 inhibition induced polyubiquitination of IKKalpha and beta during protein synthesis. In fact, GA blocked biogenesis of IKKalpha and IKKbeta but did not interfere with post-translational turnover. Together, these results define a dual requirement for Hsp90 as a regulator of NF-kappaB signaling by its general involvement in IKK activation and by its role in IKK homeostasis.
引用
收藏
页码:5378 / 5386
页数:9
相关论文
共 38 条
[31]   Crystal structure of an Hsp90-geldanamycin complex: Targeting of a protein chaperone by an antitumor agent [J].
Stebbins, CE ;
Russo, AA ;
Schneider, C ;
Rosen, N ;
Hartl, FU ;
Pavletich, NP .
CELL, 1997, 89 (02) :239-250
[32]  
Sugita T, 1999, BIOCHEM MOL BIOL INT, V47, P587
[33]   Tetrameric oligomerization of IκB kinase γ (IKKγ) is obligatory for IKK complex activity and NF-κB activation [J].
Tegethoff, S ;
Behlke, J ;
Scheidereit, C .
MOLECULAR AND CELLULAR BIOLOGY, 2003, 23 (06) :2029-2041
[34]   INHIBITION OF HEAT-SHOCK PROTEIN HSP90-PP60(V-SRC) HETEROPROTEIN COMPLEX-FORMATION BY BENZOQUINONE ANSAMYCINS - ESSENTIAL ROLE FOR STRESS PROTEINS IN ONCOGENIC TRANSFORMATION [J].
WHITESELL, L ;
MIMNAUGH, EG ;
DECOSTA, B ;
MYERS, CE ;
NECKERS, LM .
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, 1994, 91 (18) :8324-8328
[35]   RelB is required for Peyer's patch development: differential regulation of p52-RelB by lymphotoxin and TNF [J].
Yilmaz, ZB ;
Weih, DS ;
Sivakumar, V ;
Weih, F .
EMBO JOURNAL, 2003, 22 (01) :121-130
[36]   Effects of geldanamycin, a heat-shock protein 90-binding agent, on T cell function and T cell nonreceptor protein tyrosine kinases [J].
Yorgin, PD ;
Hartson, SD ;
Fellah, AM ;
Scroggins, BT ;
Huang, WJ ;
Katsanis, E ;
Couchman, JM ;
Matts, RL ;
Whitesell, L .
JOURNAL OF IMMUNOLOGY, 2000, 164 (06) :2915-2923
[37]   Hsp90: a specialized but essential protein-folding tool [J].
Young, JC ;
Moarefi, I ;
Hartl, FU .
JOURNAL OF CELL BIOLOGY, 2001, 154 (02) :267-273
[38]   Recruitment of the IKK signalosome to the p55 TNF receptor:: RIP and A20 bind to NEMO (IKKγ) upon receptor stimulation [J].
Zhang, SQ ;
Kovalenko, A ;
Cantarella, G ;
Wallach, D .
IMMUNITY, 2000, 12 (03) :301-311