Journal of Biological Chemistry
Volume 286, Issue 52, 30 December 2011, Pages 44380-44390
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Signal Transduction
Autophagy Induced by Deficiency of Sphingosine-1-phosphate Phosphohydrolase 1 Is Switched to Apoptosis by Calpain-mediated Autophagy-related Gene 5 (Atg5) Cleavage*

https://doi.org/10.1074/jbc.M111.257519Get rights and content
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Sphingosine 1-phosphate (S1P) and ceramide have been implicated in both autophagy and apoptosis. However, the roles of these sphingolipid metabolites in the links between these two processes are not completely understood. Depletion of S1P phosphohydrolase-1 (SPP1), which degrades intracellular S1P, induces the unfolded protein response and endoplasmic reticulum stress-induced autophagy (Lépine, S., Allegood, J. C., Park, M., Dent, P., Milstien, S., and Spiegel, S. (2011) Cell Death Differ. 18, 350–361). Surprisingly, however, treatment with doxorubicin, which by itself also induced autophagy, markedly reduced the extent of autophagy mediated by depletion of SPP1. Concomitantly, doxorubicin-induced apoptosis was greatly enhanced by down-regulation of SPP1. Autophagy and apoptosis seemed to be sequentially linked because inhibiting autophagy with 3-methyladenine also markedly attenuated apoptosis. Moreover, silencing Atg5 or the three sensors of the unfolded protein response, IRE1α, ATF6, and PKR-like eIF2α kinase (PERK), significantly decreased both autophagy and apoptosis. Doxorubicin stimulated calpain activity and Atg5 cleavage, which were significantly enhanced in SPP1-depleted cells. Inhibition or depletion of calpain not only suppressed Atg5 cleavage, it also markedly decreased the robust apoptosis induced by doxorubicin in SPP1-deficient cells. Importantly, doxorubicin also increased de novo synthesis of the pro-apoptotic sphingolipid metabolite ceramide. Elevation of ceramide in turn stimulated calpain; conversely, inhibiting ceramide formation suppressed Atg5 cleavage and apoptosis. Hence, doxorubicin switches protective autophagy in SPP1-depleted cells to apoptosis by calpain-mediated Atg5 cleavage.

Apoptosis
Autophagy
Calpain
ER Stress
Sphingolipid
SPP1
Ceramide
Doxorubicin
Sphingosine 1-phosphate

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*

This work was supported, in whole or in part, by National Institutes of Health Grant 5R37GM043880 from NIGMS (to S. S.).