Title

A Therapeutic Chemical Chaperone Inhibits Cholera Intoxication and Unfolding/Translocation of the Cholera Toxin A1 Subunit

Authors

Authors

M. Taylor; T. Banerjee; F. Navarro-Garcia; J. Huerta; S. Massey; M. Burlingame; A. H. Pande; S. A. Tatulian;K. Teter

Comments

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Abbreviated Journal Title

PLoS One

Keywords

RETICULUM-ASSOCIATED DEGRADATION; AMYOTROPHIC-LATERAL-SCLEROSIS; CHO-CELLS RESISTANT; ENDOPLASMIC-RETICULUM; INTRACELLULAR TRAFFICKING; THERMAL-STABILITY; EPITHELIAL-CELLS; MAMMALIAN-CELLS; PROTEIN TOXINS; CYTOSOL; Multidisciplinary Sciences

Abstract

Cholera toxin (CT) travels as an intact AB(5) protein toxin from the cell surface to the endoplasmic reticulum (ER) of an intoxicated cell. In the ER, the catalytic A1 subunit dissociates from the rest of the toxin. Translocation of CTA1 from the ER to the cytosol is then facilitated by the quality control mechanism of ER-associated degradation (ERAD). Thermal instability in the isolated CTA1 subunit generates an unfolded toxin conformation that acts as the trigger for ERAD-mediated translocation to the cytosol. In this work, we show by circular dichroism and fluorescence spectroscopy that exposure to 4-phenylbutyric acid (PBA) inhibited the thermal unfolding of CTA1. This, in turn, blocked the ER-to-cytosol export of CTA1 and productive intoxication of either cultured cells or rat ileal loops. In cell culture studies PBA did not affect CT trafficking to the ER, CTA1 dissociation from the holotoxin, or functioning of the ERAD system. PBA is currently used as a therapeutic agent to treat urea cycle disorders. Our data suggest PBA could also be used in a new application to prevent or possibly treat cholera.

Journal Title

Plos One

Volume

6

Issue/Number

4

Publication Date

1-1-2011

Document Type

Article

Language

English

First Page

11

WOS Identifier

WOS:000289671100025

ISSN

1932-6203

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