FIGURE 7: Overview of macrolide antibiotics activate the ISR. Macrolide antibiotics inhibit lysosomal acidification, leading to the blockade of autophagic flux and the accumulation of unfolded or misfolded proteins. Moreover, they induce the accumulation of ROS. The combined accumulation of unfolded/misfolded proteins and ROS induces an ISR, including the activation of PeIF2α/ATF4/CHOP signaling, XBP1 splicing, and ATF6 translocation, which in turn contribute to the translocation of TFEB and TFE3. Furthermore, TFEB and TFE3 are involved in the accumulation of LC3B-bound autophagosomes and the activation of ATF4 and CHOP.