dc.contributor.author	Song, Dan-Dan
dc.contributor.author	Zhang, Tong-Tong
dc.contributor.author	Chen, Jia-Li
dc.contributor.author	Xia, Yun-Fei
dc.contributor.author	Qin, Zheng-Hong
dc.contributor.author	Waeber, Christian
dc.contributor.author	Sheng, Rui
dc.contributor.funder	FP7 People: Marie-Curie Actions
dc.contributor.funder	National Natural Science Foundation of China
dc.date.accessioned	2017-09-26T11:39:20Z
dc.date.available	2017-09-26T11:39:20Z
dc.date.issued	2017
dc.description.abstract	Our previous findings suggest that sphingosine kinase 2 (SPK2) mediates ischemic tolerance and autophagy in cerebral preconditioning. The aim of this study was to determine by which mechanism SPK2 activates autophagy in neural cells. In both primary murine cortical neurons and HT22 hippocampal neuronal cells, overexpression of SPK2 increased LC3II and enhanced the autophagy flux. SPK2 overexpression protected cortical neurons against oxygen glucose deprivation (OGD) injury, as evidenced by improvement of neuronal morphology, increased cell viability and reduced lactate dehydrogenase release. The inhibition of autophagy effectively suppressed the neuroprotective effect of SPK2. SPK2 overexpression reduced the co-immunoprecipitation of Beclin-1 and Bcl-2, while Beclin-1 knockdown inhibited SPK2-induced autophagy. Both co-immunoprecipitation and GST pull-down analysis suggest that SPK2 directly interacts with Bcl-2. SPK2 might interact to Bcl-2 in the cytoplasm. Notably, an SPK2 mutant with L219A substitution in its putative BH3 domain was not able to activate autophagy. A Tat peptide fused to an 18-amino acid peptide encompassing the native, but not the L219A mutated BH3 domain of SPK2 activated autophagy in neural cells. The Tat-SPK2 peptide also protected neurons against OGD injury through autophagy activation. These results suggest that SPK2 interacts with Bcl-2 via its BH3 domain, thereby dissociating it from Beclin-1 and activating autophagy. The observation that Tat-SPK2 peptide designed from the BH3 domain of SPK2 activates autophagy and protects neural cells against OGD injury suggest that this structure may provide the basis for a novel class of therapeutic agents against ischemic stroke.	en
dc.description.sponsorship	National Natural Science Foundation of China (81173057, 81373402, 81673421)	en
dc.description.status	Peer reviewed	en
dc.description.version	Published Version	en
dc.format.mimetype	application/pdf	en
dc.identifier.articleid	e2912
dc.identifier.citation	Song, D.-D., Zhang, T.-T., Chen, J.-L., Xia, Y.-F., Qin, Z.-H., Waeber, C. and Sheng, R. (2017) 'Sphingosine kinase 2 activates autophagy and protects neurons against ischemic injury through interaction with Bcl-2 via its putative BH3 domain', Cell Death and Disease, 8, e2912 (14pp). doi: 10.1038/cddis.2017.289	en
dc.identifier.doi	10.1038/cddis.2017.289
dc.identifier.issn	2041-4889
dc.identifier.journaltitle	Cell Death and Disease	en
dc.identifier.uri	https://hdl.handle.net/10468/4794
dc.identifier.volume	8
dc.language.iso	en	en
dc.publisher	Nature Publishing Group	en
dc.relation.project	info:eu-repo/grantAgreement/EC/FP7::SP3::PEOPLE/631246/EU/Sphingosine kinase 2-mediated preconditioning in stroke/SPK AND STROKE
dc.relation.uri	https://www.nature.com/cddis/journal/v8/n7/full/cddis2017289a.html
dc.rights	© 2017, the Authors. Cell Death and Disease is an open-access journal published by Nature Publishing Group. This work is licensed under a Creative Commons Attribution 4.0 International License. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in the credit line; if the material is not included under the Creative Commons license, users will need to obtain permission from the license holder to reproduce the material. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/	en
dc.rights.uri	https://creativecommons.org/licenses/by/4.0/
dc.subject	Endoplasmic reticulum stress	en
dc.subject	Cerebral ischemia	en
dc.subject	Cell death	en
dc.subject	In vitro	en
dc.subject	Beclin-1	en
dc.subject	Phosphatidylinositol 3-kinase	en
dc.subject	PARK2-dependent mitophagy	en
dc.subject	BH3 only protein	en
dc.subject	Induce autophagy	en
dc.subject	Brain injury	en
dc.title	Sphingosine kinase 2 activates autophagy and protects neurons against ischemic injury through interaction with Bcl-2 via its putative BH3 domain	en
dc.type	Article (peer-reviewed)	en

Sphingosine kinase 2 activates autophagy and protects neurons against ischemic injury through interaction with Bcl-2 via its putative BH3 domain

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