Regulation of dioxin receptor function by the Hsp90 chaperone complex
Author: Kazlauskas, Arunas
Date: 2002-04-12
Location: Föreläsningssalen, Institutionen för Cell och Molekylär Biologi, Berzelius väg 21
Time: 9.30
Department: Institutionen för cell- och molekylärbiologi (CMB) / Department of Cell and Molecular Biology
Abstract
In mammals the basic helix-loop-helix/Per-Arnt-Sim (bHLH/PAS) family of transcription factors includes the dioxin receptor which is a ligand-dependent transcription factor which mediates biological effects of environmental pollutants such as 2,3,7,8-tetrachlorodibenzo-rho-dioxin (dioxin). In the absence of ligand, the dioxin receptor is associated with the molecular chaperone Hsp90 and two Hsp90-interacting proteins, the co-chaperone p23 and an immunophilin-like protein XAP2. The interaction of Hsp90 with the receptor is required to maintain the nonactivated form of the dioxin receptor in a high-affinity ligand-binding and repressed conformation.
In our studies we have demonstrated that the stability of the latent, p23associated dioxin receptor-Hsp90 complex, is critical determinant for ligand-iducible activation of the receptor to a functional form. Furthermore, the molecular chaperone Hsp90 complex regulate intracellular localization of the dioxin receptor. More specifically, ligand-inducible nuclear import of the dioxin receptor is regulated by the Hsp90-p23 complex via modulation of the interaction of the NLS motif of the receptor with importin-alpha (pendulin). Moreover, the association of the Hsp90 complex with the PAS domain of the dioxin receptor is required to maintain a pool of the nonactivated receptor in the cell cytoplasm. Cytoplasmic accumulation of the dioxin receptor complex is mediated by a novel Hsp90-interacting protein XAP2.
In addition, XAP2 has a role in stabilizing protein levels of the dioxin receptor by inhibiting ubiquitination of the receptor. Recently we have demonstrated that the C-terminal part of XAP2 is required to directly contact Hsp90, whereas the N-terminal portion of XAP2 serves as an interaction site for the dioxin receptor complex and plays a role in stabilizing the ternary dioxin receptor-Hsp90-XAP2 complex. In addition, the integrity of the N-terminal region of XAP2 is essential for XAP2 to regulate intracellular localization of the dioxin receptor.
These studies provide a basis for our understanding of regulation of protein function by the still enigmatic and intricate Hsp90 molecular chaperone machinery. This is illustrated by the complex mechanism of conditional regulation of dioxin receptor function which is critically dependent on the interaction with the Hsp90 chaperone complex.
In our studies we have demonstrated that the stability of the latent, p23associated dioxin receptor-Hsp90 complex, is critical determinant for ligand-iducible activation of the receptor to a functional form. Furthermore, the molecular chaperone Hsp90 complex regulate intracellular localization of the dioxin receptor. More specifically, ligand-inducible nuclear import of the dioxin receptor is regulated by the Hsp90-p23 complex via modulation of the interaction of the NLS motif of the receptor with importin-alpha (pendulin). Moreover, the association of the Hsp90 complex with the PAS domain of the dioxin receptor is required to maintain a pool of the nonactivated receptor in the cell cytoplasm. Cytoplasmic accumulation of the dioxin receptor complex is mediated by a novel Hsp90-interacting protein XAP2.
In addition, XAP2 has a role in stabilizing protein levels of the dioxin receptor by inhibiting ubiquitination of the receptor. Recently we have demonstrated that the C-terminal part of XAP2 is required to directly contact Hsp90, whereas the N-terminal portion of XAP2 serves as an interaction site for the dioxin receptor complex and plays a role in stabilizing the ternary dioxin receptor-Hsp90-XAP2 complex. In addition, the integrity of the N-terminal region of XAP2 is essential for XAP2 to regulate intracellular localization of the dioxin receptor.
These studies provide a basis for our understanding of regulation of protein function by the still enigmatic and intricate Hsp90 molecular chaperone machinery. This is illustrated by the complex mechanism of conditional regulation of dioxin receptor function which is critically dependent on the interaction with the Hsp90 chaperone complex.
List of papers:
I. Kazlauskas A, Poellinger L, Pongratz I (1999). Evidence that the co-chaperone p23 regulates ligand responsiveness of the dioxin (Aryl hydrocarbon) receptor. J Biol Chem. 274(19): 13519-24.
Pubmed
II. Kazlauskas A, Poellinger L, Pongratz I (2000). The immunophilin-like protein XAP2 regulates ubiquitination and subcellular localization of the dioxin receptor. J Biol Chem. 275(52): 41317-24.
Pubmed
III. Kazlauskas A, Sundstrom S, Poellinger L, Pongratz I (2001). The hsp90 chaperone complex regulates intracellular localization of the dioxin receptor. Mol Cell Biol. 21(7): 2594-607.
Pubmed
IV. Kazlauskas A, Poellinger L, Pongratz I (2002). Two distinct regions of the immunophilin-like protein XAP2 regulate dioxin receptor function and interaction with hsp90. J Biol Chem.
Pubmed
I. Kazlauskas A, Poellinger L, Pongratz I (1999). Evidence that the co-chaperone p23 regulates ligand responsiveness of the dioxin (Aryl hydrocarbon) receptor. J Biol Chem. 274(19): 13519-24.
Pubmed
II. Kazlauskas A, Poellinger L, Pongratz I (2000). The immunophilin-like protein XAP2 regulates ubiquitination and subcellular localization of the dioxin receptor. J Biol Chem. 275(52): 41317-24.
Pubmed
III. Kazlauskas A, Sundstrom S, Poellinger L, Pongratz I (2001). The hsp90 chaperone complex regulates intracellular localization of the dioxin receptor. Mol Cell Biol. 21(7): 2594-607.
Pubmed
IV. Kazlauskas A, Poellinger L, Pongratz I (2002). Two distinct regions of the immunophilin-like protein XAP2 regulate dioxin receptor function and interaction with hsp90. J Biol Chem.
Pubmed
Issue date: 2002-03-22
Publication year: 2002
ISBN: 91-7349-176-4
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