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Regulation of Autophagy by Sphingosine‐1‐Phosphate Phosphohydrolase 1
Author(s) -
Lepine Sandrine,
Schramm Danielle,
Milstien Sheldon,
Spiegel Sarah
Publication year - 2009
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.23.1_supplement.520.8
Subject(s) - downregulation and upregulation , autophagy , microbiology and biotechnology , sphingosine , chemistry , pi3k/akt/mtor pathway , unfolded protein response , sphingosine 1 phosphate , signal transduction , intracellular , biology , endoplasmic reticulum , apoptosis , receptor , biochemistry , gene
Sphingolipid metabolites have recently been implicated in autophagy. In this work, we showed that downregulation of sphingosine‐1‐phosphate phosphohydrolase 1 (SPP1), an enzyme that dephosphorylates S1P induced autophagy, as determined by increased formation of LC3‐positive autophagosomes and immunoblotting for LC3II. Downregulation of PERK, IRE1_, or ATF6, three initiators of ER stress signaling, suppressed autophagy mediated by SPP1 depletion. Moreover, CHOP, Bip and phospho‐eif2, and cleavage of pro‐caspase 4 and pro‐caspase 2, downstream targets of ER and Golgi stress, was increased after downregulation of SPP1. However, silencing SPP1 did not affect either beclin levels or mTor downstream targets, suggesting that these pathways are not involved. Interestingly, downregulation of SPP1 did not lead to apoptosis. Exogenous S1P or dihydro‐S1P, which activate S1P receptors, in contrast to increased intracellular S1P, do not induce autophagy. Thus, SPP1 may regulate protective autophagy through ER stress signaling by regulation of intracellular S1P levels. Supported by R37GM043880 to SS.