Novel effects of Brefeldin A (BFA) in signaling through the insulin receptor (IR) pathway and regulating FoxO1-mediated transcription

Abstract

Brefeldin A (BFA) is a fungal metabolite best known for its ability to inhibit activation of ADP-ribosylation factor (Arf) and thereby inhibit secretory traffic. BFA also appears to regulate the trafficking of the GLUT4 glucose transporter by inducing its relocation from intracellular stores to the cell surface. Such redistribution of GLUT4 is normally regulated by insulin-mediated signaling. Hence, we tested whether BFA may intersect with the insulin pathway. We report that BFA causes the activation of the insulin receptor (IR), IRS-1, Akt-2, and AS160 components of the insulin pathway. The response is mediated through phosphoinositol-3-kinase (PI3K) and Akt kinase since the PI3K inhibitor wortmannin and the Akt inhibitors MK2206 and perifosine inhibit the BFA effect. BFA-mediated activation of the insulin pathway results in Akt-mediated phosphorylation of the insulin-responsive transcription factor FoxO1. This leads to nuclear exclusion of FoxO1 and a decrease in transcription of the insulin-responsive gene SIRT-1. Our findings suggest novel effects for BFA in signaling and transcription, and imply that BFA has multiple intracellular targets and can be used to regulate diverse cellular responses that include vesicular trafficking, signaling and transcription.

Functional disruption of the Golgi apparatus protein ARF1 sensitizes MDA-MB-231 breast cancer cells to the antitumor drugs Actinomycin D and Vinblastine through ERK and AKT signaling

“…Because microtubules play an important role in membrane trafficking [ 105 ], this synergistic effect could be the result of VLB adding an impact on the secretory pathway. The effect of BFA in MDA-MB-231 cells is also in contrast to its effect in differentiated 3T3-L1 adipocytes, which results in an increase in the levels of phospho-AKT [ 106 ], or in human keratinocytes, which results in no change in the levels of phospho-AKT [ 107 ]. These observations indicate that BFA in different cell types might have several, distinct targets that are related in different fashions to the AKT signaling pathway.…”

The Fungal Metabolite Brefeldin A Inhibits Dvl2-Plk1-Dependent Primary Cilium Disassembly

“…Therefore, we cannot rule out the possibility of BFA controlling ciliogenesis, by regulation of the ER-Golgi system, as well as primary cilium disassembly inhibition, by regulation of the Dvl2-Plk1 complex, as identified in this study. Since the transcriptional repressions by blockage of Golgi-dependent vesicular transport have been reported ( Kingsbury and Cardenas, 2016 ; Pahl and Baeuerle, 1995 ; Wyrozumska et al, 2014 ), we speculate that BFA may inhibit the Plk1 mRNA expression via the blockage of vesicular trafficking-induced cytoplasmic-nuclear translocation of some transcription factor which induces Plk1 expression. However, the exact mechanism is needed to be elucidated in further study.…”

A quadratically regularized functional canonical correlation analysis for identifying the global structure of pleiotropy with NGS data

“…DOCK7 , which presented associations with the 46 traits (p-value ≤ 4.42 × 10 −57 ), HsCRP (p-value ≤ 3.66 × 10 −53 ) and BMI (p-value ≤ 9.36 × 10 −7 ), has been associated with heart disease and ischemic stroke [ 76 ] and overweight and obesity[ 77 ]. Gene GBF1 , which was associated with the 46 traits (p-value ≤ 6.30 × 10 −28 ), HOMA-B (p-value ≤ 2.91 × 10 −17 ), has been reported to be involved in insulin resistance and type 2 diabetes [ 78 ]. METAP2 , which showed strong association with the 46 traits (p-value ≤ 2.62 × 10 −20 ), HOMA-B (p-value ≤ 3.14 × 10 −32 ), HOMA-IR (p-value ≤ 3.17 × 10 −17 ) and insulin (p-value ≤ 8.61 × 10 −10 ), has demonstrated associations with insulin resistance and insulin levels [ 79 ].…”