Sphingosine-1-phosphate phosphohydrolase-1 regulates ER stress-induced autophagy.
The sphingolipid metabolites ceramide and sphingosine-1-phosphate (S1P) have recently been implicated in autophagy. In this study, we report that depletion of sphingosine-1-phosphate phosphohydrolase-1 (SPP1), an endoplasmic reticulum (ER)-resident enzyme that specifically dephosphorylates S1P, induced autophagy. Although the mammalian target of rapamycin and class III phosphoinositide 3-kinase/Beclin-1 pathways were not involved and this autophagy was p53 independent, C/EBP homologous protein, BiP, and phospho-eucaryotic translation initiation factor-2α, and cleavage of procaspases 2 and 4, downstream targets of ER stress, were increased after SPP1 depletion. Autophagy was suppressed by depletion of protein kinase regulated by RNA-like ER kinase (PERK), inositol-requiring transmembrane kinase/endonuclease-1α, or activating transcription factor 6, three sensors of the unfolded protein response (UPR) to ER stress. Autophagy triggered by downregulation of SPP1 did not lead to apoptosis but rather stimulated, in a PERK dependent manner, the survival signal Akt, whose inhibition then sensitized cells to apoptosis. Although depletion of SPP1 increased intracellular levels of S1P and its secretion, activation of cell surface S1P receptors did not induce autophagy. Nevertheless, increases in intracellular pools of S1P, but not dihydro-S1P, induced autophagy and ER stress. Thus, SPP1, by regulating intracellular S1P homeostasis, can control the UPR and ER stress-induced autophagy.
Lépine
S
S
Department of Biochemistry and Molecular Biology and the Massey Cancer Center, Virginia Commonwealth University School of Medicine, 1101 E. Marshall Street, Richmond, VA 23298, USA.
Allegood
J C
JC
Park
M
M
Dent
P
P
Milstien
S
S
Spiegel
S
S
D001343:Autophagy; D045744:Cell Line, Tumor; D015536:Down-Regulation; D004721:Endoplasmic Reticulum / Q000201:enzymology* / Q000378:metabolism; D006801:Humans; D008246:Lysophospholipids / Q000378:metabolism*; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism*; D010744:Phosphoric Monoester Hydrolases / Q000235:genetics / Q000378:metabolism*; D010766:Phosphorylation; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D034622:RNA Interference; D034741:RNA, Small Interfering; D013110:Sphingosine / Q000031:analogs & derivatives* / Q000378:metabolism; D058570:TOR Serine-Threonine Kinases / Q000378:metabolism; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism; D019892:eIF-2 Kinase / Q000378:metabolism
D008246:Lysophospholipids; D008565:Membrane Proteins; D010744:Phosphoric Monoester Hydrolases; D051057:Proto-Oncogene Proteins c-akt; D034741:RNA, Small Interfering; D013110:Sphingosine; D058570:TOR Serine-Threonine Kinases; D016159:Tumor Suppressor Protein p53; D019892:eIF-2 Kinase; C060506:sphingosine 1-phosphate; C546842:MTOR protein, human; C498527:SGPP1 protein, human
Curr Biol. 1998 Oct 22;8(21):1195-8
9799739
J Cell Biol. 1998 Jul 13;142(1):229-40
9660876
J Biol Chem. 2004 Nov 19;279(47):49420-9
15339911
Mol Cell Biol. 2006 Jul;26(13):5055-69
16782891
Nat Rev Mol Cell Biol. 2007 Sep;8(9):741-52
17717517
J Biol Chem. 2007 Aug 17;282(33):24131-45
17580304
Cell Death Differ. 2007 Sep;14(9):1576-82
17612585
Cancer Res. 2009 Dec 15;69(24):9346-53
19934311
Nature. 1999 Dec 9;402(6762):672-6
10604474
Biochim Biophys Acta. 2006 Dec;1758(12):1864-84
17052686
J Cell Biol. 2002 Sep 16;158(6):1039-49
12235122
Cell Death Differ. 2009 Jul;16(7):966-75
19325568
Nature. 1996 Jun 27;381(6585):800-3
8657285
Biochem J. 1999 Sep 15;342 Pt 3:667-75
10477278
Cell. 2008 Jan 11;132(1):27-42
18191218
J Biol Chem. 2004 Apr 30;279(18):18384-91
14970205
J Biol Chem. 2006 Mar 31;281(13):8518-27
16415355
Proc Natl Acad Sci U S A. 1998 Jan 6;95(1):150-5
9419344
Mol Cell Endocrinol. 2008 Feb 13;283(1-2):104-13
18191017
Annu Rev Biochem. 2005;74:739-89
15952902
J Biol Chem. 2007 May 11;282(19):14165-77
17379599
Mol Biol Cell. 2007 Sep;18(9):3635-44
17596516
J Biol Chem. 2009 Jan 30;284(5):2719-2728
19029119
Nat Rev Mol Cell Biol. 2008 Feb;9(2):139-50
18216770
Nat Rev Mol Cell Biol. 2003 May;4(5):397-407
12728273
Cancer Biol Ther. 2008 Oct;7(10):1648-62
18787411
J Biol Chem. 2003 Sep 5;278(36):34541-7
12815058
Science. 2004 Nov 5;306(5698):990-5
15528435
Cell Death Differ. 2008 Sep;15(9):1460-71
18551133
Mol Pharmacol. 2006 Aug;70(2):589-603
16622074
Science. 2009 Sep 4;325(5945):1254-7
19729656
Nat Rev Drug Discov. 2008 Dec;7(12):1013-30
19043451
Autophagy. 2007 Jan-Feb;3(1):45-7
17035732
Nat Cell Biol. 2008 Jun;10(6):676-87
18454141
Nature. 2000 Jan 6;403(6765):98-103
10638761
Oncogene. 2009 Feb 12;28(6):910-20
19029953
J Cell Biol. 2008 Oct 6;183(1):101-16
18838554
Mol Cell Biol. 2006 Dec;26(24):9220-31
17030611
EMBO J. 2000 Nov 1;19(21):5720-8
11060023
Cancer Res. 1999 Dec 15;59(24):6185-91
10626811
Mol Cell. 2009 Sep 11;35(5):551-61
19748352
Cell Death Differ. 2003 Oct;10(10):1188-203
14502242