Golgicide A reveals essential roles for GBF1 in Golgi assembly and function.
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.
Sáenz
José B
JB
Department of Pediatrics, Washington University School of Medicine, 660 S. Euclid Ave., St. Louis, Missouri 63110, USA.
Sun
William J
WJ
Chang
Jae Won
JW
Li
Jinmei
J
Bursulaya
Badry
B
Gray
Nathanael S
NS
Haslam
David B
DB
D000818:Animals; D002522:Chlorocebus aethiops; D020755:Coat Protein Complex I / Q000378:metabolism; D004285:Dogs; D004705:Endocytosis; D006056:Golgi Apparatus / Q000187:drug effects* / Q000378:metabolism / Q000502:physiology; D020662:Guanine Nucleotide Exchange Factors / Q000502:physiology*; D006801:Humans; D009682:Magnetic Resonance Spectroscopy; D013058:Mass Spectrometry; D011725:Pyridines / Q000494:pharmacology*; D011804:Quinolines / Q000494:pharmacology*; D022621:Shiga Toxin / Q000037:antagonists & inhibitors* / Q000633:toxicity; D014709:Vero Cells
D020755:Coat Protein Complex I; C120445:GBF1 protein, human; D020662:Guanine Nucleotide Exchange Factors; D011725:Pyridines; D011804:Quinolines; C539165:golgicide A; D022621:Shiga Toxin