Figure 2.

Inducers and inhibitors of CMA. Targeting the chaperone: One potential approach to modulate CMA involves the direct targeting of the chaperone such as Hsp90. Through the inhibition of the ATPase activity of Hsp90, Geldanamycin acts as an inducer of CMA. Conversely, the synthetic peptide p140 targets and hampers the chaperone function of Hsc70, acting as an inhibitor. Modulation of LAMP-2A levels: The expression of LAMP-2A is directly connected to the level of CMA. Reactive oxygen species (ROS) target the activation of transcription factor, NFAT-1 leading to its recruitment on the LAMP-2 promoter followed by an upregulation of its expression. Modulation of oxidative stress constitutes another potential approach to modulating CMA. Inducer of ROS, such as 6-AN, upregulates the level of CMA while vitamin E is a powerful antioxidant reducing or restoring its basal level. The mTORC2/PHLPP1/AKT pathway: The mTORC2/AKT1/PHLPP1 axis coordinates the dynamic assembly and disassembly of LAMP-2A into multimers. Torin-1 inhibits the function of mTORC2, therefore blocking the activation of AKT, promoting the formation of LAMP-2A multimers and, finally, inducing CMA. ADAS is a small molecule that inhibits the catalytic site of PHLPP1, thus blocking its phosphatase activity on AKT1. The phosphorylation of AKT1, which in turn phosphorylates the glial fibrillary acidic protein (GFAP), negatively regulates the dynamics of LAMP-2A assembly and inhibits CMA. The ERICA pathway: The ER-stress-induced CMA (ERICA) is a pathway connecting endoplasmic reticulum (ER) stress with CMA induction through the activation of p38 MAPK. The level of CMA is decreased in the presence of SB230580, an inhibitor of the activation of the p38 MAPK.