TY - JOUR
T1 - Regulation of autophagy and its associated cell death by "sphingolipid rheostat"
T2 - Reciprocal role of ceramide and sphingosine 1-phosphate in the mammalian target of rapamycin pathway
AU - Taniguchi, Makoto
AU - Kitatani, Kazuyuki
AU - Kondo, Tadakazu
AU - Hashimoto-Nishimura, Mayumi
AU - Asano, Satoshi
AU - Hayashi, Akira
AU - Mitsutake, Susumu
AU - Igarashi, Yasuyuki
AU - Umehara, Hisanori
AU - Takeya, Hiroyuki
AU - Kigawa, Junzo
AU - Okazaki, Toshiro
PY - 2012/11/16
Y1 - 2012/11/16
N2 - The role of "sphingolipid rheostat" by ceramide and sphingosine 1-phosphate (S1P) in the regulation of autophagy remains unclear. Inhumanleukemia HL-60 cells, amino acid deprivation (AA(-)) caused autophagy with an increase in acid sphingomyleinase (SMase) activity and ceramide, which serves as an autophagy inducing lipid. Knockdown of acid SMase significantly suppressed the autophagy induction. S1P treatment counteracted autophagy induction by AA(-) or C2-ceramide. AA(-) treatment promoted mammalian target of rapamycin (mTOR) dephosphorylation/inactivation, inducing autophagy. S1P treatment suppressed mTOR inactivation and autophagy induction by AA(-). S1P exerts biological actions via cell surface receptors, and S1P3 among five S1P receptors was predominantly expressed in HL-60 cells. We evaluated the involvement of S1P3 in suppressing autophagy induction. S1P treatment of CHO cells had no effects on mTOR inactivation and autophagy induction by AA(-) or C2-ceramide. Whereas S1P treatment of S1P 3 overexpressing CHO cells resulted in activation of the mTOR pathway, preventing cells from undergoing autophagy induced by AA(-) or C 2-ceramide. These results indicate that S1P-S1P3 plays a role in counteracting ceramide signals that mediate mTOR-controlled autophagy. In addition, we evaluated the involvement of ceramide-activated protein phosphatases (CAPPs) in ceramide-dependent inactivation of the mTOR pathway. Inhibition of CAPP by okadaic acid in AA(-)- or C2-ceramide-treated cells suppressed dephosphorylation/inactivation of mTOR, autophagy induction, and autophagy-associated cell death, indicating a novel role of ceramide-CAPPs in autophagy induction. Moreover, S1P3 engagement by S1P counteracted cell death. Taken together, these results indicated that sphingolipid rheostat in ceramide-CAPPs and S1P-S1P3 signaling modulates autophagy and its associated cell death through regulation of the mTOR pathway.
AB - The role of "sphingolipid rheostat" by ceramide and sphingosine 1-phosphate (S1P) in the regulation of autophagy remains unclear. Inhumanleukemia HL-60 cells, amino acid deprivation (AA(-)) caused autophagy with an increase in acid sphingomyleinase (SMase) activity and ceramide, which serves as an autophagy inducing lipid. Knockdown of acid SMase significantly suppressed the autophagy induction. S1P treatment counteracted autophagy induction by AA(-) or C2-ceramide. AA(-) treatment promoted mammalian target of rapamycin (mTOR) dephosphorylation/inactivation, inducing autophagy. S1P treatment suppressed mTOR inactivation and autophagy induction by AA(-). S1P exerts biological actions via cell surface receptors, and S1P3 among five S1P receptors was predominantly expressed in HL-60 cells. We evaluated the involvement of S1P3 in suppressing autophagy induction. S1P treatment of CHO cells had no effects on mTOR inactivation and autophagy induction by AA(-) or C2-ceramide. Whereas S1P treatment of S1P 3 overexpressing CHO cells resulted in activation of the mTOR pathway, preventing cells from undergoing autophagy induced by AA(-) or C 2-ceramide. These results indicate that S1P-S1P3 plays a role in counteracting ceramide signals that mediate mTOR-controlled autophagy. In addition, we evaluated the involvement of ceramide-activated protein phosphatases (CAPPs) in ceramide-dependent inactivation of the mTOR pathway. Inhibition of CAPP by okadaic acid in AA(-)- or C2-ceramide-treated cells suppressed dephosphorylation/inactivation of mTOR, autophagy induction, and autophagy-associated cell death, indicating a novel role of ceramide-CAPPs in autophagy induction. Moreover, S1P3 engagement by S1P counteracted cell death. Taken together, these results indicated that sphingolipid rheostat in ceramide-CAPPs and S1P-S1P3 signaling modulates autophagy and its associated cell death through regulation of the mTOR pathway.
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U2 - 10.1074/jbc.M112.416552
DO - 10.1074/jbc.M112.416552
M3 - Article
C2 - 23035115
AN - SCOPUS:84869208878
VL - 287
SP - 39898
EP - 39910
JO - Journal of Biological Chemistry
JF - Journal of Biological Chemistry
SN - 0021-9258
IS - 47
ER -