Figure 8.

Long-term autophagy favors MTORC2 activation leading to enhanced CTGF production and myofibroblast differentiation. Short-term serum starvation inactivates MTORC1 and MTORC2 signaling leading to dephosphorylation of RPS6KB1 (Thr389) and AKT (Ser473). MTORC1 inhibition induces autophagy, demonstrated by a higher LC3B-II/-I ratio and lower SQSTM1 level. Rapamycin increases autophagy by further inhibiting MTORC1. A sustained autophagic response is responsible for the MTORC2 reactivation when fibroblasts are starved for 2 d or more (long term), as measured by rephosphorylation of AKT at Ser473. In turn, MTORC2 activity drives the production and secretion of the pro-fibrotic cytokine CTGF leading to myofibroblast differentiation. Long-term exposure to rapamycin inactivates MTORC1 leading to an increased autophagic response, but prevents MTORC2 activation and downstream CTGF induction and myofibroblast differentiation.