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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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.date.accessioned 2017-09-26T11:39:20Z
dc.date.available 2017-09-26T11:39:20Z
dc.date.issued 2017
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.volume 8
dc.identifier.issn 2041-4889
dc.identifier.uri http://hdl.handle.net/10468/4794
dc.identifier.doi 10.1038/cddis.2017.289
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.format.mimetype application/pdf en
dc.language.iso en en
dc.publisher Nature Publishing Group en
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
dc.internal.authorcontactother Christian Waeber, Pharmacy, University College Cork, Cork, Ireland. +353-21-490-3000 Email: c.waeber@ucc.ie en
dc.internal.availability Full text available en
dc.description.version Published Version en
dc.internal.wokid WOS:000406870400001
dc.contributor.funder FP7 People: Marie-Curie Actions
dc.contributor.funder National Natural Science Foundation of China
dc.description.status Peer reviewed en
dc.identifier.journaltitle Cell Death and Disease en
dc.internal.IRISemailaddress c.waeber@ucc.ie en
dc.identifier.articleid e2912
dc.relation.project info:eu-repo/grantAgreement/EC/FP7::SP3::PEOPLE/631246/EU/Sphingosine kinase 2-mediated preconditioning in stroke/SPK AND STROKE


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© 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/ Except where otherwise noted, this item's license is described as © 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/
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