LG186: An Inhibitor of GBF1 Function that Causes Golgi Disassembly in Human and Canine Cells |
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| Authors: | Frédéric Boal Lucie Guetzoyan Richard B. Sessions Mahel Zeghouf Robert A. Spooner J. Michael Lord Jacqueline Cherfils Guy J. Clarkson Lynne M. Roberts David J. Stephens |
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| Affiliation: | 1. Cell Biology Laboratories, School of Biochemistry, Medical Sciences Building, University of Bristol, University Walk, Bristol BS8 1TD, UK;2. Department of Biological Sciences, University of Warwick, Gibbet Hill Road, Coventry CV4 7AL, UK;3. Department of Chemistry, University of Warwick, Gibbet Hill Road, Coventry CV4 7AL, UK;4. School of Biochemistry, Medical Sciences Building, University of Bristol, University Walk, Bristol BS8 1TD, UK;5. Laboratoire d’Enzymologie et Biochimie Structurales, Bat 34, CNRS, Avenue de la terrasse, 91198 Gif sur Yvette, France |
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| Abstract: | Brefeldin A‐mediated inhibition of ADP ribosylation factor (Arf) GTPases and their guanine nucleotide exchange factors, Arf‐GEFs, has been a cornerstone of membrane trafficking research for many years. Brefeldin A (BFA) is relatively non‐selective inhibiting at least three targets in human cells, Golgi brefeldin A resistance factor 1 (GBF1), brefeldin A inhibited guanine nucleotide exchange factor 1 (BIG1) and brefeldin A inhibited guanine nucleotide exchange factor 2 (BIG2). Here, we show that the previously described compound Exo2 acts through inhibition of Arf‐GEF function, but causes other phenotypic changes that are not GBF1 related. We describe the engineering of Exo2 to produce LG186, a more selective, reversible inhibitor of Arf‐GEF function. Using multiple‐cell‐based assays and GBF1 mutants, our data are most consistent with LG186 acting by selective inhibition of GBF1. Unlike other Arf‐GEF and reported GBF1 inhibitors including BFA, Exo2 and Golgicide A, LG186 induces disassembly of the Golgi stack in both human and canine cells. |
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| Keywords: | Arf‐GEF GBF1 Golgi vesicle transport |
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