Autophagy induced by deficiency of sphingosine-1-phosphate phosphohydrolase 1 is switched to apoptosis by calpain-mediated autophagy-related gene 5 (Atg5) cleavage.

摘要: Sphingosine 1-phosphate (S1P) and ceramide have been implicated in both autophagy apoptosis. However, the roles of these sphingolipid metabolites links between two processes are not completely understood. Depletion S1P phosphohydrolase-1 (SPP1), which degrades intracellular S1P, induces unfolded protein response endoplasmic reticulum stress-induced (Lepine, S., Allegood, J. C., Park, M., Dent, P., Milstien, Spiegel, S. (2011) Cell Death Differ. 18, 350–361). Surprisingly, however, treatment with doxorubicin, by itself also induced autophagy, markedly reduced extent mediated depletion SPP1. Concomitantly, doxorubicin-induced apoptosis was greatly enhanced down-regulation Autophagy seemed to be sequentially linked because inhibiting 3-methyladenine attenuated Moreover, silencing Atg5 or three sensors response, IRE1α, ATF6, PKR-like eIF2α kinase (PERK), significantly decreased Doxorubicin stimulated calpain activity cleavage, were SPP1-depleted cells. Inhibition only suppressed it robust doxorubicin SPP1-deficient Importantly, increased de novo synthesis pro-apoptotic metabolite ceramide. Elevation turn calpain; conversely, formation cleavage Hence, switches protective cells calpain-mediated cleavage.