Modulation of the stress-activated protein kinases Hog1/p38 and a TORC1-dependent kinase by curcumin is stress granule-dependent.

Curcumin, a natural polyphenolic compound, is widely recognized for its anti-inflammatory, anticancer, and antimicrobial properties. Despite its long history of medicinal use, the precise mechanisms underlying its cellular effects remain incompletely understood. In yeast, curcumin has been shown to activate Hog1, a stress-activated protein kinase (SAPK), but the regulatory basis of this activation is unclear. Here, we investigated the role of stress granules in mediating the effects of curcumin. We found that either disrupting Pub1, a core stress granule protein in yeast, or applying the stress granule dissolution agent lipoamide markedly reduced curcumin-induced Hog1 activation. Curcumin is also known to inhibit S6 phosphorylation mediated by a TORC1-dependent kinase in mammals. We found that this phenomenon occurs in yeast as well, and the effect was similarly dependent on Pub1 and lipoamide. Using the rat skeletal muscle cell line L6, we showed that lipoamide likewise dampens the effect of curcumin on p38 activation. Together, these findings identify stress granules as a critical mediator of the effects of curcumin on SAPK and S6 signaling, providing new insight into how this ancient compound modulates cellular signaling pathways.