LG186: An inhibitor of GBF1 function that causes Golgi disassembly in human and canine cells.
Traffic. 2010 Dec; 11(12):1537-51
This article reports the development and characterization of an inhibitor (LG186) of Arf-GEF function that is more selective for GBF1. LG186 induces disassembly of the Golgi without affecting endosomes in both human and canine cells. LG186 may, therefore, be a very useful small molecule inhibitor for trafficking studies involving Golgi and the secretory pathway.
Brefeldin A has been a useful chemical to study the secretory pathway as it causes many cellular changes, including very rapid tubulation of early endosomes, redistribution of endosomes and the trans-Golgi network, and fusion of these two compartments. Such widespread effects are due to inhibition of several GEFs, among them GBF1, BIG1, and BIG2. Golgicide A is a more specific inhibitor of GBF1 but appears to have a binding site that overlaps with brefeldin A. Both brefeldin A and Golgicide A are ineffective against canine GBF1 due to a single amino acid substitution within the binding domain.
The authors of this study used a model of the GBF1 Sec7 domain with docked existing inhibitors to design a new compound, LG186, with improved specificity for GBF1 over BIG1 and BIG2. The design strategy involved targeting a GBF1 tripeptide insertion that is not present in BIG1 and BIG2 but conserved between human and canine sequences. LG186 inhibition of GBF1 causes redistribution of Golgi, does not cause tubulation or enlargement of recycling or early endosomes (in agreement with no inhibition of BIG2), and does not affect localization of AP1 clathrin adaptor (as seen with brefeldin A). Due to increased specificity for both human and canine GBF1, LG186 may be a useful tool for a variety of trafficking experiments.
Some caveats are (1) complete washout and reversibility of LG186 is possible but more variable than brefeldin A and (2) LG186 is less soluble and slower-acting than Golgicide A.
Jan L and Thayer D: F1000Prime Recommendation of [Boal F et al., Traffic 2010, 11(12):1537-51]. In F1000Prime, 09 Dec 2010; DOI: 10.3410/f.6822959.6992057. F1000Prime.com/6822959#eval6992057
F1000Prime Recommendations, Dissents and Comments for [Boal F et al., Traffic 2010, 11(12):1537-51]. In F1000Prime, 11 Dec 2013; F1000Prime.com/6822959
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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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