TUDCA Modulates Drug Bioavailability to Regulate Resistance to Acute ER Stress in

Cells counter accumulation of misfolded secretory proteins in the endoplasmic reticulum (ER) through activation of the Unfolded Protein Response (UPR). Small molecules termed chemical chaperones can promote protein folding to alleviate ER stress. The bile acid tauroursodeoxycholic acid (TUDCA) has been described as a chemical chaperone. While promising in models of protein folding diseases, TUDCA's mechanism of action remains unclear. Here, we found TUDCA can rescue growth of yeast treated with the ER stressor tunicamycin (Tm), even in the absence of a functional UPR. In contrast, TUDCA failed to rescue growth on other ER stressors. Nor could TUDCA attenuate chronic UPR associated with specific gene deletions or overexpression of a misfolded mutant secretory protein. Neither pretreatment with nor delayed addition of TUDCA conferred protection against Tm. Importantly, attenuation of Tm-induced toxicity required TUDCA's critical micelle forming concentration, suggesting a mechanism where TUDCA directly sequesters drugs. Indeed, in several assays, TUDCA-treated cells closely resembled cells treated with lower doses of Tm. In addition, we found TUDCA can inhibit dyes from labeling intracellular compartments. Thus, our study challenges the model of TUDCA as a chemical chaperone and suggests that TUDCA decreases drug bioavailability, allowing cells to adapt to ER stress.