SENP3 Promotes an Mff-Primed Bcl-x L -Drp1 Interaction Involved in Cell Death Following Ischemia.

Guo, C; Hildick, KL; Jiang, J; Zhao, A; Guo, W; Henley, JM; Wilkinson, KA

SENP3 Promotes an Mff-Primed Bcl-x L -Drp1 Interaction Involved in Cell Death Following Ischemia.

Guo, C Hildick, KL Jiang, J Zhao, A Guo, W Henley, JM Wilkinson, KA

Permalink

Publisher:: Frontiers Media
Publication Type:: Journal Article
Citation:: Frontiers in Cell and Developmental Biology, 2021, 9, pp. 1-14
Issue Date:: 2021

Open Access

Copyright Clearance Process

Recently Added
In Progress
Open Access

This item is open access.

Adobe PDF

Download full textAdobe PDF (10.1 MB)

View on publisher's site

View statistics

Full metadata record

Field	Value	Language
dc.contributor.author	Guo, C
dc.contributor.author	Hildick, KL
dc.contributor.author	Jiang, J
dc.contributor.author	Zhao, A
dc.contributor.author	Guo, W
dc.contributor.author	Henley, JM
dc.contributor.author	Wilkinson, KA
dc.date.accessioned	2022-05-27T02:18:33Z
dc.date.available	2021-09-17
dc.date.available	2022-05-27T02:18:33Z
dc.date.issued	2021
dc.identifier.citation	Frontiers in Cell and Developmental Biology, 2021, 9, pp. 1-14
dc.identifier.issn	2296-634X
dc.identifier.issn	2296-634X
dc.identifier.uri	http://hdl.handle.net/10453/157743
dc.description.abstract	Dysregulation of the mitochondrial fission machinery has been linked to cell death following ischemia. Fission is largely dependent on recruitment of Dynamin-related protein 1 (Drp1) to the receptor Mitochondrial fission factor (Mff) located on the mitochondrial outer membrane (MOM). Drp1 is a target for SUMOylation and its deSUMOylation, mediated by the SUMO protease SENP3, enhances the Drp1-Mff interaction to promote cell death in an oxygen/glucose deprivation (OGD) model of ischemia. Another interacting partner for Drp1 is the Bcl-2 family member Bcl-x L , an important protein in cell death and survival pathways. Here we demonstrate that preventing Drp1 SUMOylation by mutating its SUMO target lysines enhances the Drp1-Bcl-x L interaction in vivo and in vitro. Moreover, SENP3-mediated deSUMOylation of Drp1 promotes the Drp1-Bcl-x L interaction. Our data suggest that Mff primes Drp1 binding to Bcl-x L at the mitochondria and that Mff and Bcl-x L can interact directly, independent of Drp1, through their transmembrane domains. Importantly, SENP3 loss in cells subjected to OGD correlates with reduced Drp1-Bcl-x L interaction, whilst recovery of SENP3 levels in cells subjected to reoxygenation following OGD correlates with increased Drp1-Bcl-x L interaction. Expressing a Bcl-x L mutant with defective Drp1 binding reduces OGD plus reoxygenation-evoked cell death. Taken together, our results indicate that SENP3-mediated deSUMOlyation promotes an Mff-primed Drp1-Bcl-x L interaction that contributes to cell death following ischemia.
dc.format	Electronic-eCollection
dc.language	eng
dc.publisher	Frontiers Media
dc.relation.ispartof	Frontiers in Cell and Developmental Biology
dc.relation.isbasedon	10.3389/fcell.2021.752260
dc.rights	info:eu-repo/semantics/openAccess
dc.title	SENP3 Promotes an Mff-Primed Bcl-x L -Drp1 Interaction Involved in Cell Death Following Ischemia.
dc.type	Journal Article
utslib.citation.volume	9
utslib.location.activity	Switzerland
pubs.organisational-group	/University of Technology Sydney
pubs.organisational-group	/University of Technology Sydney/Faculty of Science
pubs.organisational-group	/University of Technology Sydney/Faculty of Science/School of Life Sciences
utslib.copyright.status	open_access	*
pubs.consider-herdc	false
dc.date.updated	2022-05-27T02:18:29Z
pubs.publication-status	Published
pubs.volume	9

Abstract:

Dysregulation of the mitochondrial fission machinery has been linked to cell death following ischemia. Fission is largely dependent on recruitment of Dynamin-related protein 1 (Drp1) to the receptor Mitochondrial fission factor (Mff) located on the mitochondrial outer membrane (MOM). Drp1 is a target for SUMOylation and its deSUMOylation, mediated by the SUMO protease SENP3, enhances the Drp1-Mff interaction to promote cell death in an oxygen/glucose deprivation (OGD) model of ischemia. Another interacting partner for Drp1 is the Bcl-2 family member Bcl-x L , an important protein in cell death and survival pathways. Here we demonstrate that preventing Drp1 SUMOylation by mutating its SUMO target lysines enhances the Drp1-Bcl-x L interaction in vivo and in vitro. Moreover, SENP3-mediated deSUMOylation of Drp1 promotes the Drp1-Bcl-x L interaction. Our data suggest that Mff primes Drp1 binding to Bcl-x L at the mitochondria and that Mff and Bcl-x L can interact directly, independent of Drp1, through their transmembrane domains. Importantly, SENP3 loss in cells subjected to OGD correlates with reduced Drp1-Bcl-x L interaction, whilst recovery of SENP3 levels in cells subjected to reoxygenation following OGD correlates with increased Drp1-Bcl-x L interaction. Expressing a Bcl-x L mutant with defective Drp1 binding reduces OGD plus reoxygenation-evoked cell death. Taken together, our results indicate that SENP3-mediated deSUMOlyation promotes an Mff-primed Drp1-Bcl-x L interaction that contributes to cell death following ischemia.

Please use this identifier to cite or link to this item:

http://hdl.handle.net/10453/157743