Disease relevance of brefeldin A

• Brefeldin A, a specific inhibitor of exocytosis, completely and reversibly inhibited the presentation of viral proteins, but not exogenous peptides, to MHC class I-restricted CTLs directed against influenza virus antigens [1].
• Cells from BI-1-deficient mice, including fibroblasts, hepatocytes, and neurons, display selective hypersensitivity to apoptosis induced by ER stress agents (thapsigargin, tunicamycin, brefeldin A), but not to stimulators of mitochondrial or TNF/Fas-death receptor apoptosis pathways [2].
• In contrast, despite the translocation of apolipoprotein B48 into the endoplasmic reticulum in patients with abetalipoproteinemia and in biopsies treated with Brefeldin A, which blocks anterograde transport between the endoplasmic reticulum and the Golgi network, there was no transformation of endoglycosidase H-sensitive oligosaccharides [3].
• Transfection studies revealed that overexpression of wild-type or proteolytically inactive Lon promoted assembly of COX II into a COX I-containing complex, and partially prevented mitochondrial dysfunction caused by brefeldin A or hypoxia [4].
• GLUT2 surface expression and intracellular transport via the constitutive pathway in pancreatic beta cells and insulinoma: evidence for a block in trans-Golgi network exit by brefeldin A [5].

High impact information on brefeldin A

• Inhibition of BIG2 by BFA, or by a dominant negative ARFGEF2 cDNA, decreases cell proliferation in vitro, suggesting a cell-autonomous regulation of neural expansion [6].
• The Arabidopsis protein GNOM is a brefeldin A (BFA) sensitive ARF-GEF that is required for the proper polar localization of PIN1, a candidate transporter of the plant hormone auxin [7].
• The null mutant cells impaired lysosomal dispersion, while brefeldin A could normally induce the breakdown of their Golgi apparatus [8].
• We have found that, in vitro, endosomes recruit a characteristic set of cytoplasmic proteins in a GTP gamma S-stimulated and brefeldin A-sensitive fashion [9].
• Formation of COPI-coated, but not COPII-coated, buds and vesicles on the nuclear envelope is inhibited by the fungal metabolite brefeldin A [10].

Chemical compound and disease context of brefeldin A

• Coexpression of furin with the fowl plague virus hemagglutinin in the presence of brefeldin A and monensin reveals that furin has to enter the Golgi region to gain substrate cleaving activity [11].
• To address these possibilities, three different murine B lymphoma lines were tested for their ability to process and present native protein Ag in the presence of the protein synthesis inhibitor cycloheximide or the protein synthesis inhibitor cycloheximide or the protein export inhibitor, Brefeldin A [12].
• Differential effects of brefeldin A on chondroitin sulfate and hyaluronan synthesis in rat chondrosarcoma cells [13].
• When delivered by adenovirus, processing and presentation of CFP10 were blocked by both BFA and the proteasomal blocker lactacystin [14].
• Cerulenin inhibits the cytotoxicity of ricin, modeccin, Pseudomonas toxin, and diphtheria toxin in brefeldin A-resistant cell lines [15].

Biological context of brefeldin A

• A brefeldin A-like phenotype is induced by the overexpression of a human ERD-2-like protein, ELP-1 [16].
• Treatment of most cells with brefeldin A (BFA) leads to the retrieval of the Golgi complex to the endoplasmic reticulum, presumably reflecting an inhibition of cytoplasmic coat protein binding to Golgi membranes [17].
• Tubule formation of these organelles was specific to BFA, shared near identical pharmacologic characteristics as Golgi tubules and resulted in targeted membrane fusion [18].
• The fungal metabolite brefeldin A (BFA), an inhibitor of protein transport from the endoplasmic reticulum, inhibits presentation of endogenous antigens for MHC-restricted T-cell recognition [19].
• Brefeldin A implicates egress from endoplasmic reticulum in class I restricted antigen presentation [20].

Anatomical context of brefeldin A

• Characteristics of brefeldin A (BFA)-induced redistribution of Golgi proteins into the endoplasmic reticulum (ER) and its relationship to an ER retrieval pathway were investigated [21].
• Brefeldin A (BFA) is a fungal metabolite that causes a redistribution of the stacked cisternae of the Golgi complex into the endoplasmic reticulum by inhibiting anterograde transport [22].
• Recruitment of coat proteins onto Golgi membranes in intact and permeabilized cells: effects of brefeldin A and G protein activators [23].
• Brefeldin A causes a microtubule-mediated fusion of the trans-Golgi network and early endosomes [22].
• The observation that brefeldin A interfered with sorting but not transport in both endosomes and the Golgi further supports this [24].

Associations of brefeldin A with other chemical compounds

• Using diffusing latex beads to monitor membrane flow, we find that axonal membrane flows rapidly (7 microns/min) from growth cone to cell body during axon growth and that flow is inhibited by brefeldin A [25].
• Here we report the discovery of an enzyme in a Golgi-enriched fraction that catalyses guanine nucleotide (GDP-GTP) exchange on ARF-1 protein, and which is inhibited by brefeldin A [26].
• We show here that influenza A matrix protein can be effectively presented to class II-restricted T cells by two pathways: one of which is chloroquine-sensitive, BFA-insensitive, the other being chloroquine-insensitive and BFA-sensitive [27].
• We report here that mastoparan, a peptide that activates heterotrimeric G proteins, promotes binding of beta-COP to Golgi membranes in vitro and antagonizes the effect of brefeldin A on beta-COP in perforated cells and on isolated Golgi membranes [28].
• Recovery of TRPC3-GFP fluorescence after photobleaching of the plasma membrane region was decreased by brefeldin-A or BAPTA-AM [29].

Gene context of brefeldin A

• The exchange activity of ARNO is not inhibited by brefeldin A, an agent known to block vesicular transport and inhibit the exchange activity on ARF1 in cell extracts [30].
• Brefeldin A acts to stabilize an abortive ARF-GDP-Sec7 domain protein complex: involvement of specific residues of the Sec7 domain [31].
• Brefeldin A treatment induced further accumulation of caveolin-2 along with caveolin-1 in LD [32].
• Co-expression of PAK4 and the constitutively active Cdc42HsV12 causes the redistribution of PAK4 to the brefeldin A-sensitive compartment of the Golgi membrane and the subsequent induction of filopodia and actin polymerization [33].
• Plasma membrane and intracellular pools of AUX1 are interconnected by actin-dependent constitutive trafficking, which is not sensitive to the vesicle trafficking inhibitor brefeldin A [34].

Analytical, diagnostic and therapeutic context of brefeldin A

• The membrane-mediated budding hypothesis was inspired by the microtubule-dependent extension of apparently uncoated, 90-nm-diameter membrane tubules from the Golgi apparatus and other organelles in vivo after treatment with brefeldin A, a drug that inhibits the assembly of coat proteins onto Golgi membranes [35].
• Immunofluorescence studies with anti-ldlCp antibodies in mammalian cells established that ldlCp is a peripheral Golgi protein whose association with the Golgi is brefeldin A sensitive [36].
• Probing mitochondrial Ca2+ with recombinant aequorin confirmed that this pool did not coincide with mitochondria, whereas its homogeneous distribution across the cytosol, as revealed by confocal microscopy, and its insensitivity to brefeldin A make localization within the Golgi complex unlikely [37].
• Immunohistochemical studies on cocultures treated with brefeldin A, an inhibitor of protein secretion, indicated both epithelial and mesenchymal cells synthesize laminin alpha1 chain upon heterotypic cell- cell contact [38].
• We have studied the effects of brefeldin A (BFA) on the tubular endosomes in AtT20 and HeLa cells (Tooze, J., and M. Hollinshead. 1991. J. Cell Biol. 115:635-653) by electron microscopy of cells labeled with three endocytic tracers, HRP, BSA-gold, and transferrin conjugated to HRP, and by immunofluorescence microscopy [39].

References