TY - JOUR
T1 - Golgicide A reveals essential roles for GBF1 in Golgi assembly and function
AU - Sáenz, José B.
AU - Sun, William J.
AU - Chang, Jae Won
AU - Li, Jinmei
AU - Bursulaya, Badry
AU - Gray, Nathanael S.
AU - Haslam, David B.
N1 - Funding Information:
The authors thank S. Chiang and the Institute of Chemistry and Cellular Biology (ICCB)-Longwood staff for their assistance with screening, J. Loughman (Washington University School of Medicine) for synthesis of MDCK cell cDNA, P. Melanc¸on (University of Alberta) for providing the hamster GBF1 cDNA, M. Vaughn (US National Heart, Lung, and Blood Institute) for providing the BIG1-HA cDNA, M. Haslam for technical assistance and S. Kornfeld and G. Bu for advice and critical review of the manuscript. This work was supported by US National Institutes of Health grant U54 AI057160 to the Midwest Regional Center of Excellence for Biodefense and Emerging Infectious Diseases Research (MRCE) and by an Investigators in Microbial Pathogenesis Award from the Burroughs Wellcome Foundation.
PY - 2009/3
Y1 - 2009/3
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=60249098993&partnerID=8YFLogxK
U2 - 10.1038/nchembio.144
DO - 10.1038/nchembio.144
M3 - Article
C2 - 19182783
AN - SCOPUS:60249098993
SN - 1552-4450
VL - 5
SP - 157
EP - 165
JO - Nature Chemical Biology
JF - Nature Chemical Biology
IS - 3
ER -