Trierixin, a Novel Inhibitor of ER Stress-induced XBP1 Activation from Streptomyces sp.

Abstract

In the course of screening for an inhibitor of ER stress-induced XBP1 activation, we isolated a new member of the triene-ansamycin group compound, trierixin, from a culture broth of Streptomyces sp. AC 654. Trierixin was purified by column chromatography on silica gel and by HPLC. The molecular formula of trierixin is C 37 H 52 N 2 O 8 S. Trierixin inhibited thapsigargin-induced XBP1-luciferase activation in HeLa/XBP1-luc cells and endogenous XBP1 splicing in HeLa cells with an IC 50 of 14 ng/ml and 19 ng/ml, respectively. Moreover, in the process of isolating trierixin, we isolated structurally related mycotrienin II and trienomycin A as inhibitors of ER stress-induced XBP1 activation from a culture broth of a trierixin-producing strain. This study provides the first observation that triene-ansamycins have a novel inhibitory effect against XBP1 activation.

Quinotrierixin Inhibited ER Stress-Induced XBP1 mRNA Splicing through Inhibition of Protein Synthesis

“…We have also reported that novel trieneansamycin group compounds, quinotrierixin and trierixin, inhibited ER stress-induced XBP1 mRNA splicing in HeLa cells. [15][16][17][18] In this study, we found that quinotrierixin inhibited protein synthesis. Moreover, we investigated the relationship between quinotrierixin-inhibited ER stress-induced XBP1 mRNA splicing and protein synthesis.…”

“…As reported previously, 15) HeLa cells were seeded in 12-well plates at 5 Â 10 4 cells/well, and then incubated with 10 mg/mL of tunicamycin with and without quinotrierixin and other protein synthesis inhibitors for 4 h. Subsequently, total RNA was extracted from the HeLa cells using TRIzol reagent (Invitrogen, Carlsbad, CA). Aliquots of 2.0 mg of the total RNA were treated with M-MLV reverse transcriptase (Promega, Madison, WI) to produce first-strand cDNA, which was subjected to polymerase chain reaction (PCR) with KOD plus polymerase (Toyobo, Osaka, Japan) using a pair of primers corresponding to nucleotides 505-524 and 609-629 of XBP1 cDNA.…”

“…Quinotrierixin, trierixin, and trienomycin A were prepared as described in our previous reports. 15,17) Cytotrienin A was kindly provided by Dr. H. Osada (RIKEN, Japan). Cycloheximide, anisomycin, and puromycin were purchased from Sigma (St. Louis, MO).…”

Endoplasmic reticulum stress and intestinal inflammation

“…are known to secrete small molecules such as macrocytic lactams (e.g., trierixin), which directly inhibit XBP1 activation. 54 Similarly, Shiga toxigenic Escherichia coli secrete AB 5 cytotoxins that activate ER stress pathways by direct cleavage of grp78. 55 These and other examples show how there may be a bidirectional interaction between ER stress pathways within the epithelium and the microbial communities contained within the lumen, suggesting that different genotypes may converge phenotypically on ER stress pathways via effects on the intestinal microbiota.…”

ER stress transcription factor Xbp1 suppresses intestinal tumorigenesis and directs intestinal stem cells

“…In this rapidly renewing tissue that is constantly exposed to noxious stimuli that may impact protein folding, Xbp1 may not only assist in resolving ER stress but may thereby keep the regenerative response, including stem cell activation, in check. However, overwhelming the remedial abilities of Xbp1 (e.g., through genetic hypofunction of Xbp1 or persistence of microbial or environmental ER stressors including those that inhibit Xbp1 function; Tashiro et al, 2007) may initiate a compensatory regenerative response, which is facilitative of neoplasias if persistent. In line with this, the architecture of ISCs in close proximity to Paneth cells is preserved in tumors , which we speculate might result in a situation in which the increase in ISCs and proliferative output in Xbp1 /(IEC) tumors may outcompete any potential survival disadvantage of differentiated epithelial cells caused by Xbp1 deficiency.…”