Trierixin, a novel inhibitor of ER stress-induced XBP1 activation from Streptomyces sp.

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 C37H52N2O8S. Trierixin inhibited thapsigargin-induced XBP1-luciferase activation in HeLa/XBP1-1uc cells and endogenous XBP1 splicing in HeLa cells with an IC50 of 14 ng/ml and 19 ng/ml, respectively. Moreover, in the process of isolating trierixin, we isolated structurally related mycotrienin 11 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.