LG186: An inhibitor of GBF1 function that causes Golgi disassembly in human and canine cells

F Boal, L Guetzoyan, RB Sessions, M Zeghouf, RA Spooner, JM Lord, J Cherfils, GJ Clarkson, LM Roberts, DJ Stephens

Research output: Contribution to journalArticle (Academic Journal)peer-review

28 Citations (Scopus)

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.
Translated title of the contributionLG186: An inhibitor of GBF1 function that causes Golgi disassembly in human and canine cells
Original languageEnglish
Pages (from-to)1537 - 1551
Number of pages15
JournalTraffic
Volume11 (12)
DOIs
Publication statusPublished - Dec 2010

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