Authors

M. Taylor; F. Navarro-Garcia; J. Huerta; H. Burress; S. Massey; K. Ireton;K. Teter

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Abbreviated Journal Title

J. Biol. Chem.

Keywords

PROTEIN-DEGRADATION PATHWAY; CELL CHAPERONE HSP90; BOTULINUM C2 TOXIN; RETRO-TRANSLOCATION; MAMMALIAN-CELLS; INTRACELLULAR TRAFFICKING; CYSTIC-FIBROSIS; CULTURED-CELLS; RETROTRANSLOCATION; POLYPEPTIDE; Biochemistry & Molecular Biology

Abstract

Cholera toxin (CT) is an AB(5) toxin that moves from the cell surface to the endoplasmic reticulum (ER) by retrograde vesicular transport. In the ER, the catalytic A1 subunit dissociates from the rest of the toxin and enters the cytosol by exploiting the quality control system of ER-associated degradation (ERAD). The driving force for CTA1 dislocation into the cytosol is unknown. Here, we demonstrate that the cytosolic chaperone Hsp90 is required for CTA1 passage into the cytosol. Hsp90 bound to CTA1 in an ATP-dependent manner that was blocked by geldanamycin (GA), an established Hsp90 inhibitor. CT activity against cultured cells and ileal loops was also blocked by GA, as was the ER-to-cytosol export of CTA1. Experiments using RNA interference or N-ethylcarboxamidoadenosine, a drug that inhibits ER-localized GRP94 but not cytosolic Hsp90, confirmed that the inhibitory effects of GA resulted specifically from the loss of Hsp90 activity. This work establishes a functional role for Hsp90 in the ERAD-mediated dislocation of CTA1.

Journal Title

Journal of Biological Chemistry

Volume

285

Issue/Number

41

Publication Date

1-1-2010

Document Type

Article

Language

English

First Page

31261

Last Page

31267

WOS Identifier

WOS:000282764600020

ISSN

0021-9258

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