Article abstract
Nature Chemical Biology 5, 157 - 165 (2009)
Published online: 1 February 2009 | doi:10.1038/nchembio.144
Golgicide A reveals essential roles for GBF1 in Golgi assembly and function
José B Sáenz1,2,6, William J Sun1,2,6, Jae Won Chang3,4, Jinmei Li1,2, Badry Bursulaya5, Nathanael S Gray3,4 & David B Haslam1,2
Abstract
ADP ribosylation factor 1 (Arf1) plays a critical role in regulating secretory traffic and membrane transport within the Golgi of eukaryotic cells. Arf1 is activated by guanine nucleotide exchange factors (ArfGEFs), which confer spatial and temporal specificity to vesicular transport. We describe here the discovery and characterization of golgicide A, a potent, highly specific, reversible inhibitor of the cis-Golgi ArfGEF GBF1. Inhibition of GBF1 function resulted in rapid dissociation of COPI vesicle coat from Golgi membranes and subsequent disassembly of the Golgi and trans-Golgi network. Secretion of soluble and membrane-associated proteins was arrested at the endoplasmic reticulum–Golgi intermediate compartment, whereas endocytosis and recycling of transferrin were unaffected by GBF1 inhibition. Internalized shiga toxin was arrested within the endocytic compartment and was unable to reach the dispersed trans-Golgi network. Collectively, these results highlight the central role for GBF1 in coordinating bidirectional transport and maintaining structural integrity of the Golgi.
- Department of Pediatrics, Washington University School of Medicine, 660 S. Euclid Ave., St. Louis, Missouri 63110, USA.
- Department of Molecular Microbiology, Washington University School of Medicine, 660 S. Euclid Ave., St. Louis, Missouri 63110, USA.
- Department of Cancer Biology, Dana Farber Cancer Institute, 44 Binney Street, Boston, Massachusetts 02115, USA.
- Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, 250 Longwood Ave., Boston, Massachusetts 02115, USA.
- Genomics Institute of the Novartis Research Foundation, 10675 John Jay Hopkins Drive, San Diego, California 92121, USA.
- These authors contributed equally to this work.
Correspondence to: David B Haslam1,2 e-mail: haslam@kids.wustl.edu
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