Fig. 3: Regulatory role of S1P in the core process of autophagy.

S1P is synthesized in the cell and transported to the extracellular space through SPNS2 or ABC. By coupling with Gi/o, S1P/S1PRs activate the PI3K/Akt/mTOR pathway. mTOR signaling phosphorylates the ULK1 complex to inhibit autophagy initiation. Besides, S1PR2 activates the G (12/13) /Rho/Rho kinase/PTEN pathway and leads to Akt inhibition. During vesicle nucleation, S1P/S1PR3 signaling upregulates the expression and phosphorylation of Bcl-2. The binding of Bcl-2 to Beclin1 helps Beclin1 escape from the PI3KC3 complex, leading to the failure of recruiting other autophagic proteins. PE functions as an anchor to phagophore membranes for LC3 to maintain vesicle elongation and maturation. Through directly interacting with S1P degradation product CDP-ethanolamine, PE connects S1P metabolism and autophagy regulation. The intracellular accumulation of S1P participates in the control of lysosome function by regulating lysosome calcium storage and the activity of lysosome-related membrane protein LAMP, thus regulating autophagosome-lysosome fusion. Finally, the fusion of autophagosome and lysosome provides a membrane source of SM for the production of S1P. Created with figdraw.com. PCYT2 ethanolamine, LAMP lysosome-associated membrane protein.