Gene/Protein Disease Symptom Drug Enzyme Compound
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Using three different trans dominant mutants of bovine ARF1 affecting GDP exchange or GTP hydrolysis we demonstrate the central role of ARF1 in controlling vesicular traffic from the endoplasmic reticulum (ER) to the Golgi apparatus and between successive Golgi compartments. Overexpression of ARF1(Q71L), a mutant likely to be restricted to the GTP-bound form, resulted in the accumulation of vesicular stomatitis virus glycoprotein in pre-Golgi intermediates, inhibited transport between successive Golgi compartments, and led to a striking association of beta-COP with pre-Golgi intermediates and the Golgi stack. In contrast, ARF1(T31N), a mutant which is likely to have a preferential affinity for GDP compared to the wild-type protein, inhibited export from the ER and triggered a brefeldin A-like phenotype, resulting in the redistribution of beta-COP from Golgi membranes to the cytosol and the collapse of the Golgi into the ER. This mutant, which may efficiently sequester an ARF-specific guanine nucleotide-exchange protein (ARF-GEF), suggests that ARF and ARF-GEF are essential for export from the ER. These results are discussed in the context of the GDP and GTP-bound forms of ARF in controlling both membrane structure and vesicular traffic through the early secretory pathway.
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PMID:Dominant inhibitory mutants of ARF1 block endoplasmic reticulum to Golgi transport and trigger disassembly of the Golgi apparatus. 828 10

A phenotypic screen was used to search for drug-like molecules that can interfere with specific steps in membrane traffic. 2-(4-Fluorobenzoylamino)-benzoic acid methyl ester (Exo1), identified in this screen, induces a rapid collapse of the Golgi to the endoplasmic reticulum, thus acutely inhibiting the traffic emanating from the endoplasmic reticulum. Like Brefeldin A (BFA), Exo1 induces the rapid release of ADP-ribosylation factor (ARF) 1 from Golgi membranes but has less effect on the organization of the trans-Golgi network. Our data indicate that Exo1 acts by a different mechanism from BFA. Unlike BFA, Exo1 does not induce the ADP-ribosylation of CtBP/Bars50 and does not interfere with the activity of guanine nucleotide exchange factors specific for Golgi-based ARFs. Thus, Exo1 allows the fatty acid exchange activity of Bars50 to be distinguished from ARF1 activity in the control of Golgi tubulation.
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PMID:Exo1: a new chemical inhibitor of the exocytic pathway. 1273 86

The organization and sorting of proteins within the Golgi stack to establish and maintain its cis to trans polarization remains an enigma. The function of Golgi compartments involves coat assemblages that facilitate vesicle traffic, Rab-tether-SNAP receptor (SNARE) machineries that dictate membrane identity, as well as matrix components that maintain structure. We have investigated how the Golgi complex achieves compartmentalization in response to a key component of the coat complex I (COPI) coat assembly pathway, the ARF1 GTPase, in relationship to GTPases-regulating endoplasmic reticulum (ER) exit (Sar1) and targeting fusion (Rab1). Following collapse of the Golgi into the ER in response to inhibition of activation of ARF1 by Brefeldin A, we found that Sar1- and Rab1-dependent Golgi reformation took place at multiple peripheral and perinuclear ER exit sites. These rapidly converged into immature Golgi that appeared as onion-like structures composed of multiple concentrically arrayed cisternae of mixed enzyme composition. During clustering to the perinuclear region, Golgi enzymes were sorted to achieve the degree of polarization within the stack found in mature Golgi. Surprisingly, we found that sorting of Golgi enzymes into their subcompartments was insensitive to the dominant negative GTP-restricted ARF1 mutant, a potent inhibitor of COPI coat disassembly and vesicular traffic. We suggest that a COPI-independent, Rab-dependent mechanism is involved in the rapid reorganization of resident enzymes within the Golgi stack following synchronized release from the ER, suggesting an important role for Rab hubs in directing Golgi polarization.
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PMID:The role of ARF1 and rab GTPases in polarization of the Golgi stack. 1610 83

Treatment of cells with brefeldin A (BFA) blocks secretory vesicle transport and causes a collapse of the Golgi apparatus. To gain more insight into the cellular mechanisms mediating BFA toxicity, we conducted a genome-wide haploid genetic screen that led to the identification of the small G protein ADP-ribosylation factor 4 (ARF4). ARF4 depletion preserves viability, Golgi integrity and cargo trafficking in the presence of BFA, and these effects depend on the guanine nucleotide exchange factor GBF1 and other ARF isoforms including ARF1 and ARF5. ARF4 knockdown cells show increased resistance to several human pathogens including Chlamydia trachomatis and Shigella flexneri. Furthermore, ARF4 expression is induced when cells are exposed to several Golgi-disturbing agents and requires the CREB3 (also known as Luman or LZIP) transcription factor, whose downregulation mimics ARF4 loss. Thus, we have uncovered a CREB3-ARF4 signalling cascade that may be part of a Golgi stress response set in motion by stimuli compromising Golgi capacity.
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PMID:A CREB3-ARF4 signalling pathway mediates the response to Golgi stress and susceptibility to pathogens. 2418 78