Parkin inhibits BAK and BAX apoptotic function by distinct mechanisms during mitophagy

Abstract The E3 ubiquitin ligase Parkin is a key effector of the removal of damaged mitochondria by mitophagy. Parkin determines cell fate in response to mitochondrial damage, with its loss promoting early onset Parkinson's disease and potentially also cancer progression. Controlling a cell...
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Autor*in:	Bernardini, Jonathan P [verfasserIn] Brouwer, Jason M [verfasserIn] Tan, Iris KL [verfasserIn] Sandow, Jarrod J [verfasserIn] Huang, Shuai [verfasserIn] Stafford, Che A [verfasserIn] Bankovacki, Aleksandra [verfasserIn] Riffkin, Christopher D [verfasserIn] Wardak, Ahmad Z [verfasserIn] Czabotar, Peter E [verfasserIn] Lazarou, Michael [verfasserIn] Dewson, Grant [verfasserIn]

Format:	E-Artikel
Sprache:	Englisch

Erschienen:	2018

Schlagwörter:	apoptosis BAK BAX mitophagy Parkin

Anmerkung:	© The Author(s) 2018

Übergeordnetes Werk:	Enthalten in: The EMBO Journal - Nature Publishing Group UK, 2023, 38(2018), 2 vom: 20. Dez.
Übergeordnetes Werk:	volume:38 ; year:2018 ; number:2 ; day:20 ; month:12

Links:	Volltext

DOI / URN:	10.15252/embj.201899916

Katalog-ID:	SPR058016554

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100	1		\|a Bernardini, Jonathan P \|e verfasserin \|4 aut
245	1	0	\|a Parkin inhibits BAK and BAX apoptotic function by distinct mechanisms during mitophagy
264		1	\|c 2018
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520			\|a Abstract The E3 ubiquitin ligase Parkin is a key effector of the removal of damaged mitochondria by mitophagy. Parkin determines cell fate in response to mitochondrial damage, with its loss promoting early onset Parkinson's disease and potentially also cancer progression. Controlling a cell's apoptotic response is essential to co‐ordinate the removal of damaged mitochondria. We report that following mitochondrial damage‐induced mitophagy, Parkin directly ubiquitinates the apoptotic effector protein BAK at a conserved lysine in its hydrophobic groove, a region that is crucial for BAK activation by BH3‐only proteins and its homo‐dimerisation during apoptosis. Ubiquitination inhibited BAK activity by impairing its activation and the formation of lethal BAK oligomers. Parkin also suppresses BAX‐mediated apoptosis, but in the absence of BAX ubiquitination suggesting an indirect mechanism. In addition, we find that BAK‐dependent mitochondrial outer membrane permeabilisation during apoptosis promotes PINK1‐dependent Parkin activation. Hence, we propose that Parkin directly inhibits BAK to suppress errant apoptosis, thereby allowing the effective clearance of damaged mitochondria, but also promotes clearance of apoptotic mitochondria to limit their potential pro‐inflammatory effect.
520			\|a Synopsis The ubiquitin ligase Parkin plays a protective role in neurodegenerative disease by removing damaged mitochondria and preventing apoptosis, and by limiting the functions of pro‐apoptotic effector proteins BAK and BAX. Defective control of apoptosis may contribute to the pathogenesis of early onset Parkinson's Disease caused by Parkin mutations. Parkin activity is induced by mitochondrial damage during apoptosis.Parkin mono‐ and di‐ubiquitinates BAK at a conserved lysine in its hydrophobic groove.Ubiquitination reduces BAK oligomerisation and apoptotic activity on mitochondria.Parkin prevents BAX mitochondrial localisation and apoptotic activity independent of ubiquitination.Certain Parkinson's Disease‐associated Parkin mutants cannot ubiquitinate BAK and restrain it on mitochondria.
520			\|a Graphical Abstract Autophagic clearance of damaged mitochondria and suppression of apoptotic effector proteins are coordinated functions of the Parkin ubiquitin ligase that are lost upon Parkinson's Disease‐associated mutations.
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700	1		\|a Dewson, Grant \|e verfasserin \|0 (orcid)0000-0003-4251-8898 \|4 aut
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Indexfelder

author_variant	j p b jp jpb j m b jm jmb i k t ik ikt j j s jj jjs s h sh c a s ca cas a b ab c d r cd cdr a z w az azw p e c pe pec m l ml g d gd
matchkey_str	article:14602075:2018----::aknniisaadaaottcucinyitnteh
hierarchy_sort_str	2018
publishDate	2018
allfields	10.15252/embj.201899916 doi (DE-627)SPR058016554 (SPR)embj.201899916-e DE-627 ger DE-627 rakwb eng Bernardini, Jonathan P verfasserin aut Parkin inhibits BAK and BAX apoptotic function by distinct mechanisms during mitophagy 2018 Text txt rdacontent Computermedien c rdamedia Online-Ressource cr rdacarrier © The Author(s) 2018 Abstract The E3 ubiquitin ligase Parkin is a key effector of the removal of damaged mitochondria by mitophagy. Parkin determines cell fate in response to mitochondrial damage, with its loss promoting early onset Parkinson's disease and potentially also cancer progression. Controlling a cell's apoptotic response is essential to co‐ordinate the removal of damaged mitochondria. We report that following mitochondrial damage‐induced mitophagy, Parkin directly ubiquitinates the apoptotic effector protein BAK at a conserved lysine in its hydrophobic groove, a region that is crucial for BAK activation by BH3‐only proteins and its homo‐dimerisation during apoptosis. Ubiquitination inhibited BAK activity by impairing its activation and the formation of lethal BAK oligomers. Parkin also suppresses BAX‐mediated apoptosis, but in the absence of BAX ubiquitination suggesting an indirect mechanism. In addition, we find that BAK‐dependent mitochondrial outer membrane permeabilisation during apoptosis promotes PINK1‐dependent Parkin activation. Hence, we propose that Parkin directly inhibits BAK to suppress errant apoptosis, thereby allowing the effective clearance of damaged mitochondria, but also promotes clearance of apoptotic mitochondria to limit their potential pro‐inflammatory effect. Synopsis The ubiquitin ligase Parkin plays a protective role in neurodegenerative disease by removing damaged mitochondria and preventing apoptosis, and by limiting the functions of pro‐apoptotic effector proteins BAK and BAX. Defective control of apoptosis may contribute to the pathogenesis of early onset Parkinson's Disease caused by Parkin mutations. Parkin activity is induced by mitochondrial damage during apoptosis.Parkin mono‐ and di‐ubiquitinates BAK at a conserved lysine in its hydrophobic groove.Ubiquitination reduces BAK oligomerisation and apoptotic activity on mitochondria.Parkin prevents BAX mitochondrial localisation and apoptotic activity independent of ubiquitination.Certain Parkinson's Disease‐associated Parkin mutants cannot ubiquitinate BAK and restrain it on mitochondria. Graphical Abstract Autophagic clearance of damaged mitochondria and suppression of apoptotic effector proteins are coordinated functions of the Parkin ubiquitin ligase that are lost upon Parkinson's Disease‐associated mutations. apoptosis (dpeaa)DE-He213 BAK (dpeaa)DE-He213 BAX (dpeaa)DE-He213 mitophagy (dpeaa)DE-He213 Parkin (dpeaa)DE-He213 Brouwer, Jason M verfasserin aut Tan, Iris KL verfasserin aut Sandow, Jarrod J verfasserin aut Huang, Shuai verfasserin aut Stafford, Che A verfasserin aut Bankovacki, Aleksandra verfasserin aut Riffkin, Christopher D verfasserin aut Wardak, Ahmad Z verfasserin aut Czabotar, Peter E verfasserin aut Lazarou, Michael verfasserin (orcid)0000-0003-2150-5545 aut Dewson, Grant verfasserin (orcid)0000-0003-4251-8898 aut Enthalten in The EMBO Journal Nature Publishing Group UK, 2023 38(2018), 2 vom: 20. Dez. (DE-627)266022529 (DE-600)1467419-1 1460-2075 nnns volume:38 year:2018 number:2 day:20 month:12 https://dx.doi.org/10.15252/embj.201899916 X:SPRINGER Resolving-System lizenzpflichtig Volltext SYSFLAG_0 GBV_SPRINGER GBV_ILN_20 GBV_ILN_22 GBV_ILN_23 GBV_ILN_24 GBV_ILN_31 GBV_ILN_32 GBV_ILN_39 GBV_ILN_40 GBV_ILN_62 GBV_ILN_63 GBV_ILN_65 GBV_ILN_69 GBV_ILN_70 GBV_ILN_72 GBV_ILN_73 GBV_ILN_74 GBV_ILN_90 GBV_ILN_95 GBV_ILN_100 GBV_ILN_101 GBV_ILN_105 GBV_ILN_110 GBV_ILN_120 GBV_ILN_138 GBV_ILN_150 GBV_ILN_151 GBV_ILN_161 GBV_ILN_168 GBV_ILN_170 GBV_ILN_171 GBV_ILN_187 GBV_ILN_211 GBV_ILN_213 GBV_ILN_224 GBV_ILN_230 GBV_ILN_252 GBV_ILN_266 GBV_ILN_285 GBV_ILN_293 GBV_ILN_602 GBV_ILN_636 GBV_ILN_702 GBV_ILN_2001 GBV_ILN_2003 GBV_ILN_2004 GBV_ILN_2005 GBV_ILN_2006 GBV_ILN_2007 GBV_ILN_2008 GBV_ILN_2009 GBV_ILN_2010 GBV_ILN_2011 GBV_ILN_2014 GBV_ILN_2015 GBV_ILN_2018 GBV_ILN_2020 GBV_ILN_2021 GBV_ILN_2025 GBV_ILN_2026 GBV_ILN_2027 GBV_ILN_2034 GBV_ILN_2037 GBV_ILN_2038 GBV_ILN_2044 GBV_ILN_2048 GBV_ILN_2049 GBV_ILN_2050 GBV_ILN_2055 GBV_ILN_2056 GBV_ILN_2057 GBV_ILN_2059 GBV_ILN_2061 GBV_ILN_2064 GBV_ILN_2068 GBV_ILN_2088 GBV_ILN_2093 GBV_ILN_2106 GBV_ILN_2108 GBV_ILN_2110 GBV_ILN_2111 GBV_ILN_2113 GBV_ILN_2118 GBV_ILN_2119 GBV_ILN_2122 GBV_ILN_2129 GBV_ILN_2143 GBV_ILN_2144 GBV_ILN_2147 GBV_ILN_2148 GBV_ILN_2152 GBV_ILN_2153 GBV_ILN_2188 GBV_ILN_2190 GBV_ILN_2232 GBV_ILN_2336 GBV_ILN_2470 GBV_ILN_2472 GBV_ILN_2507 GBV_ILN_2522 GBV_ILN_2548 GBV_ILN_4012 GBV_ILN_4029 GBV_ILN_4035 GBV_ILN_4037 GBV_ILN_4046 GBV_ILN_4112 GBV_ILN_4116 GBV_ILN_4125 GBV_ILN_4126 GBV_ILN_4155 GBV_ILN_4242 GBV_ILN_4246 GBV_ILN_4249 GBV_ILN_4251 GBV_ILN_4305 GBV_ILN_4306 GBV_ILN_4307 GBV_ILN_4311 GBV_ILN_4313 GBV_ILN_4314 GBV_ILN_4318 GBV_ILN_4322 GBV_ILN_4323 GBV_ILN_4324 GBV_ILN_4325 GBV_ILN_4326 GBV_ILN_4328 GBV_ILN_4333 GBV_ILN_4334 GBV_ILN_4335 GBV_ILN_4336 GBV_ILN_4338 GBV_ILN_4367 GBV_ILN_4393 GBV_ILN_4598 GBV_ILN_4700 AR 38 2018 2 20 12
spelling	10.15252/embj.201899916 doi (DE-627)SPR058016554 (SPR)embj.201899916-e DE-627 ger DE-627 rakwb eng Bernardini, Jonathan P verfasserin aut Parkin inhibits BAK and BAX apoptotic function by distinct mechanisms during mitophagy 2018 Text txt rdacontent Computermedien c rdamedia Online-Ressource cr rdacarrier © The Author(s) 2018 Abstract The E3 ubiquitin ligase Parkin is a key effector of the removal of damaged mitochondria by mitophagy. Parkin determines cell fate in response to mitochondrial damage, with its loss promoting early onset Parkinson's disease and potentially also cancer progression. Controlling a cell's apoptotic response is essential to co‐ordinate the removal of damaged mitochondria. We report that following mitochondrial damage‐induced mitophagy, Parkin directly ubiquitinates the apoptotic effector protein BAK at a conserved lysine in its hydrophobic groove, a region that is crucial for BAK activation by BH3‐only proteins and its homo‐dimerisation during apoptosis. Ubiquitination inhibited BAK activity by impairing its activation and the formation of lethal BAK oligomers. Parkin also suppresses BAX‐mediated apoptosis, but in the absence of BAX ubiquitination suggesting an indirect mechanism. In addition, we find that BAK‐dependent mitochondrial outer membrane permeabilisation during apoptosis promotes PINK1‐dependent Parkin activation. Hence, we propose that Parkin directly inhibits BAK to suppress errant apoptosis, thereby allowing the effective clearance of damaged mitochondria, but also promotes clearance of apoptotic mitochondria to limit their potential pro‐inflammatory effect. Synopsis The ubiquitin ligase Parkin plays a protective role in neurodegenerative disease by removing damaged mitochondria and preventing apoptosis, and by limiting the functions of pro‐apoptotic effector proteins BAK and BAX. Defective control of apoptosis may contribute to the pathogenesis of early onset Parkinson's Disease caused by Parkin mutations. Parkin activity is induced by mitochondrial damage during apoptosis.Parkin mono‐ and di‐ubiquitinates BAK at a conserved lysine in its hydrophobic groove.Ubiquitination reduces BAK oligomerisation and apoptotic activity on mitochondria.Parkin prevents BAX mitochondrial localisation and apoptotic activity independent of ubiquitination.Certain Parkinson's Disease‐associated Parkin mutants cannot ubiquitinate BAK and restrain it on mitochondria. Graphical Abstract Autophagic clearance of damaged mitochondria and suppression of apoptotic effector proteins are coordinated functions of the Parkin ubiquitin ligase that are lost upon Parkinson's Disease‐associated mutations. apoptosis (dpeaa)DE-He213 BAK (dpeaa)DE-He213 BAX (dpeaa)DE-He213 mitophagy (dpeaa)DE-He213 Parkin (dpeaa)DE-He213 Brouwer, Jason M verfasserin aut Tan, Iris KL verfasserin aut Sandow, Jarrod J verfasserin aut Huang, Shuai verfasserin aut Stafford, Che A verfasserin aut Bankovacki, Aleksandra verfasserin aut Riffkin, Christopher D verfasserin aut Wardak, Ahmad Z verfasserin aut Czabotar, Peter E verfasserin aut Lazarou, Michael verfasserin (orcid)0000-0003-2150-5545 aut Dewson, Grant verfasserin (orcid)0000-0003-4251-8898 aut Enthalten in The EMBO Journal Nature Publishing Group UK, 2023 38(2018), 2 vom: 20. Dez. (DE-627)266022529 (DE-600)1467419-1 1460-2075 nnns volume:38 year:2018 number:2 day:20 month:12 https://dx.doi.org/10.15252/embj.201899916 X:SPRINGER Resolving-System lizenzpflichtig Volltext SYSFLAG_0 GBV_SPRINGER GBV_ILN_20 GBV_ILN_22 GBV_ILN_23 GBV_ILN_24 GBV_ILN_31 GBV_ILN_32 GBV_ILN_39 GBV_ILN_40 GBV_ILN_62 GBV_ILN_63 GBV_ILN_65 GBV_ILN_69 GBV_ILN_70 GBV_ILN_72 GBV_ILN_73 GBV_ILN_74 GBV_ILN_90 GBV_ILN_95 GBV_ILN_100 GBV_ILN_101 GBV_ILN_105 GBV_ILN_110 GBV_ILN_120 GBV_ILN_138 GBV_ILN_150 GBV_ILN_151 GBV_ILN_161 GBV_ILN_168 GBV_ILN_170 GBV_ILN_171 GBV_ILN_187 GBV_ILN_211 GBV_ILN_213 GBV_ILN_224 GBV_ILN_230 GBV_ILN_252 GBV_ILN_266 GBV_ILN_285 GBV_ILN_293 GBV_ILN_602 GBV_ILN_636 GBV_ILN_702 GBV_ILN_2001 GBV_ILN_2003 GBV_ILN_2004 GBV_ILN_2005 GBV_ILN_2006 GBV_ILN_2007 GBV_ILN_2008 GBV_ILN_2009 GBV_ILN_2010 GBV_ILN_2011 GBV_ILN_2014 GBV_ILN_2015 GBV_ILN_2018 GBV_ILN_2020 GBV_ILN_2021 GBV_ILN_2025 GBV_ILN_2026 GBV_ILN_2027 GBV_ILN_2034 GBV_ILN_2037 GBV_ILN_2038 GBV_ILN_2044 GBV_ILN_2048 GBV_ILN_2049 GBV_ILN_2050 GBV_ILN_2055 GBV_ILN_2056 GBV_ILN_2057 GBV_ILN_2059 GBV_ILN_2061 GBV_ILN_2064 GBV_ILN_2068 GBV_ILN_2088 GBV_ILN_2093 GBV_ILN_2106 GBV_ILN_2108 GBV_ILN_2110 GBV_ILN_2111 GBV_ILN_2113 GBV_ILN_2118 GBV_ILN_2119 GBV_ILN_2122 GBV_ILN_2129 GBV_ILN_2143 GBV_ILN_2144 GBV_ILN_2147 GBV_ILN_2148 GBV_ILN_2152 GBV_ILN_2153 GBV_ILN_2188 GBV_ILN_2190 GBV_ILN_2232 GBV_ILN_2336 GBV_ILN_2470 GBV_ILN_2472 GBV_ILN_2507 GBV_ILN_2522 GBV_ILN_2548 GBV_ILN_4012 GBV_ILN_4029 GBV_ILN_4035 GBV_ILN_4037 GBV_ILN_4046 GBV_ILN_4112 GBV_ILN_4116 GBV_ILN_4125 GBV_ILN_4126 GBV_ILN_4155 GBV_ILN_4242 GBV_ILN_4246 GBV_ILN_4249 GBV_ILN_4251 GBV_ILN_4305 GBV_ILN_4306 GBV_ILN_4307 GBV_ILN_4311 GBV_ILN_4313 GBV_ILN_4314 GBV_ILN_4318 GBV_ILN_4322 GBV_ILN_4323 GBV_ILN_4324 GBV_ILN_4325 GBV_ILN_4326 GBV_ILN_4328 GBV_ILN_4333 GBV_ILN_4334 GBV_ILN_4335 GBV_ILN_4336 GBV_ILN_4338 GBV_ILN_4367 GBV_ILN_4393 GBV_ILN_4598 GBV_ILN_4700 AR 38 2018 2 20 12
allfields_unstemmed	10.15252/embj.201899916 doi (DE-627)SPR058016554 (SPR)embj.201899916-e DE-627 ger DE-627 rakwb eng Bernardini, Jonathan P verfasserin aut Parkin inhibits BAK and BAX apoptotic function by distinct mechanisms during mitophagy 2018 Text txt rdacontent Computermedien c rdamedia Online-Ressource cr rdacarrier © The Author(s) 2018 Abstract The E3 ubiquitin ligase Parkin is a key effector of the removal of damaged mitochondria by mitophagy. Parkin determines cell fate in response to mitochondrial damage, with its loss promoting early onset Parkinson's disease and potentially also cancer progression. Controlling a cell's apoptotic response is essential to co‐ordinate the removal of damaged mitochondria. We report that following mitochondrial damage‐induced mitophagy, Parkin directly ubiquitinates the apoptotic effector protein BAK at a conserved lysine in its hydrophobic groove, a region that is crucial for BAK activation by BH3‐only proteins and its homo‐dimerisation during apoptosis. Ubiquitination inhibited BAK activity by impairing its activation and the formation of lethal BAK oligomers. Parkin also suppresses BAX‐mediated apoptosis, but in the absence of BAX ubiquitination suggesting an indirect mechanism. In addition, we find that BAK‐dependent mitochondrial outer membrane permeabilisation during apoptosis promotes PINK1‐dependent Parkin activation. Hence, we propose that Parkin directly inhibits BAK to suppress errant apoptosis, thereby allowing the effective clearance of damaged mitochondria, but also promotes clearance of apoptotic mitochondria to limit their potential pro‐inflammatory effect. Synopsis The ubiquitin ligase Parkin plays a protective role in neurodegenerative disease by removing damaged mitochondria and preventing apoptosis, and by limiting the functions of pro‐apoptotic effector proteins BAK and BAX. Defective control of apoptosis may contribute to the pathogenesis of early onset Parkinson's Disease caused by Parkin mutations. Parkin activity is induced by mitochondrial damage during apoptosis.Parkin mono‐ and di‐ubiquitinates BAK at a conserved lysine in its hydrophobic groove.Ubiquitination reduces BAK oligomerisation and apoptotic activity on mitochondria.Parkin prevents BAX mitochondrial localisation and apoptotic activity independent of ubiquitination.Certain Parkinson's Disease‐associated Parkin mutants cannot ubiquitinate BAK and restrain it on mitochondria. Graphical Abstract Autophagic clearance of damaged mitochondria and suppression of apoptotic effector proteins are coordinated functions of the Parkin ubiquitin ligase that are lost upon Parkinson's Disease‐associated mutations. apoptosis (dpeaa)DE-He213 BAK (dpeaa)DE-He213 BAX (dpeaa)DE-He213 mitophagy (dpeaa)DE-He213 Parkin (dpeaa)DE-He213 Brouwer, Jason M verfasserin aut Tan, Iris KL verfasserin aut Sandow, Jarrod J verfasserin aut Huang, Shuai verfasserin aut Stafford, Che A verfasserin aut Bankovacki, Aleksandra verfasserin aut Riffkin, Christopher D verfasserin aut Wardak, Ahmad Z verfasserin aut Czabotar, Peter E verfasserin aut Lazarou, Michael verfasserin (orcid)0000-0003-2150-5545 aut Dewson, Grant verfasserin (orcid)0000-0003-4251-8898 aut Enthalten in The EMBO Journal Nature Publishing Group UK, 2023 38(2018), 2 vom: 20. Dez. (DE-627)266022529 (DE-600)1467419-1 1460-2075 nnns volume:38 year:2018 number:2 day:20 month:12 https://dx.doi.org/10.15252/embj.201899916 X:SPRINGER Resolving-System lizenzpflichtig Volltext SYSFLAG_0 GBV_SPRINGER GBV_ILN_20 GBV_ILN_22 GBV_ILN_23 GBV_ILN_24 GBV_ILN_31 GBV_ILN_32 GBV_ILN_39 GBV_ILN_40 GBV_ILN_62 GBV_ILN_63 GBV_ILN_65 GBV_ILN_69 GBV_ILN_70 GBV_ILN_72 GBV_ILN_73 GBV_ILN_74 GBV_ILN_90 GBV_ILN_95 GBV_ILN_100 GBV_ILN_101 GBV_ILN_105 GBV_ILN_110 GBV_ILN_120 GBV_ILN_138 GBV_ILN_150 GBV_ILN_151 GBV_ILN_161 GBV_ILN_168 GBV_ILN_170 GBV_ILN_171 GBV_ILN_187 GBV_ILN_211 GBV_ILN_213 GBV_ILN_224 GBV_ILN_230 GBV_ILN_252 GBV_ILN_266 GBV_ILN_285 GBV_ILN_293 GBV_ILN_602 GBV_ILN_636 GBV_ILN_702 GBV_ILN_2001 GBV_ILN_2003 GBV_ILN_2004 GBV_ILN_2005 GBV_ILN_2006 GBV_ILN_2007 GBV_ILN_2008 GBV_ILN_2009 GBV_ILN_2010 GBV_ILN_2011 GBV_ILN_2014 GBV_ILN_2015 GBV_ILN_2018 GBV_ILN_2020 GBV_ILN_2021 GBV_ILN_2025 GBV_ILN_2026 GBV_ILN_2027 GBV_ILN_2034 GBV_ILN_2037 GBV_ILN_2038 GBV_ILN_2044 GBV_ILN_2048 GBV_ILN_2049 GBV_ILN_2050 GBV_ILN_2055 GBV_ILN_2056 GBV_ILN_2057 GBV_ILN_2059 GBV_ILN_2061 GBV_ILN_2064 GBV_ILN_2068 GBV_ILN_2088 GBV_ILN_2093 GBV_ILN_2106 GBV_ILN_2108 GBV_ILN_2110 GBV_ILN_2111 GBV_ILN_2113 GBV_ILN_2118 GBV_ILN_2119 GBV_ILN_2122 GBV_ILN_2129 GBV_ILN_2143 GBV_ILN_2144 GBV_ILN_2147 GBV_ILN_2148 GBV_ILN_2152 GBV_ILN_2153 GBV_ILN_2188 GBV_ILN_2190 GBV_ILN_2232 GBV_ILN_2336 GBV_ILN_2470 GBV_ILN_2472 GBV_ILN_2507 GBV_ILN_2522 GBV_ILN_2548 GBV_ILN_4012 GBV_ILN_4029 GBV_ILN_4035 GBV_ILN_4037 GBV_ILN_4046 GBV_ILN_4112 GBV_ILN_4116 GBV_ILN_4125 GBV_ILN_4126 GBV_ILN_4155 GBV_ILN_4242 GBV_ILN_4246 GBV_ILN_4249 GBV_ILN_4251 GBV_ILN_4305 GBV_ILN_4306 GBV_ILN_4307 GBV_ILN_4311 GBV_ILN_4313 GBV_ILN_4314 GBV_ILN_4318 GBV_ILN_4322 GBV_ILN_4323 GBV_ILN_4324 GBV_ILN_4325 GBV_ILN_4326 GBV_ILN_4328 GBV_ILN_4333 GBV_ILN_4334 GBV_ILN_4335 GBV_ILN_4336 GBV_ILN_4338 GBV_ILN_4367 GBV_ILN_4393 GBV_ILN_4598 GBV_ILN_4700 AR 38 2018 2 20 12
allfieldsGer	10.15252/embj.201899916 doi (DE-627)SPR058016554 (SPR)embj.201899916-e DE-627 ger DE-627 rakwb eng Bernardini, Jonathan P verfasserin aut Parkin inhibits BAK and BAX apoptotic function by distinct mechanisms during mitophagy 2018 Text txt rdacontent Computermedien c rdamedia Online-Ressource cr rdacarrier © The Author(s) 2018 Abstract The E3 ubiquitin ligase Parkin is a key effector of the removal of damaged mitochondria by mitophagy. Parkin determines cell fate in response to mitochondrial damage, with its loss promoting early onset Parkinson's disease and potentially also cancer progression. Controlling a cell's apoptotic response is essential to co‐ordinate the removal of damaged mitochondria. We report that following mitochondrial damage‐induced mitophagy, Parkin directly ubiquitinates the apoptotic effector protein BAK at a conserved lysine in its hydrophobic groove, a region that is crucial for BAK activation by BH3‐only proteins and its homo‐dimerisation during apoptosis. Ubiquitination inhibited BAK activity by impairing its activation and the formation of lethal BAK oligomers. Parkin also suppresses BAX‐mediated apoptosis, but in the absence of BAX ubiquitination suggesting an indirect mechanism. In addition, we find that BAK‐dependent mitochondrial outer membrane permeabilisation during apoptosis promotes PINK1‐dependent Parkin activation. Hence, we propose that Parkin directly inhibits BAK to suppress errant apoptosis, thereby allowing the effective clearance of damaged mitochondria, but also promotes clearance of apoptotic mitochondria to limit their potential pro‐inflammatory effect. Synopsis The ubiquitin ligase Parkin plays a protective role in neurodegenerative disease by removing damaged mitochondria and preventing apoptosis, and by limiting the functions of pro‐apoptotic effector proteins BAK and BAX. Defective control of apoptosis may contribute to the pathogenesis of early onset Parkinson's Disease caused by Parkin mutations. Parkin activity is induced by mitochondrial damage during apoptosis.Parkin mono‐ and di‐ubiquitinates BAK at a conserved lysine in its hydrophobic groove.Ubiquitination reduces BAK oligomerisation and apoptotic activity on mitochondria.Parkin prevents BAX mitochondrial localisation and apoptotic activity independent of ubiquitination.Certain Parkinson's Disease‐associated Parkin mutants cannot ubiquitinate BAK and restrain it on mitochondria. Graphical Abstract Autophagic clearance of damaged mitochondria and suppression of apoptotic effector proteins are coordinated functions of the Parkin ubiquitin ligase that are lost upon Parkinson's Disease‐associated mutations. apoptosis (dpeaa)DE-He213 BAK (dpeaa)DE-He213 BAX (dpeaa)DE-He213 mitophagy (dpeaa)DE-He213 Parkin (dpeaa)DE-He213 Brouwer, Jason M verfasserin aut Tan, Iris KL verfasserin aut Sandow, Jarrod J verfasserin aut Huang, Shuai verfasserin aut Stafford, Che A verfasserin aut Bankovacki, Aleksandra verfasserin aut Riffkin, Christopher D verfasserin aut Wardak, Ahmad Z verfasserin aut Czabotar, Peter E verfasserin aut Lazarou, Michael verfasserin (orcid)0000-0003-2150-5545 aut Dewson, Grant verfasserin (orcid)0000-0003-4251-8898 aut Enthalten in The EMBO Journal Nature Publishing Group UK, 2023 38(2018), 2 vom: 20. Dez. (DE-627)266022529 (DE-600)1467419-1 1460-2075 nnns volume:38 year:2018 number:2 day:20 month:12 https://dx.doi.org/10.15252/embj.201899916 X:SPRINGER Resolving-System lizenzpflichtig Volltext SYSFLAG_0 GBV_SPRINGER GBV_ILN_20 GBV_ILN_22 GBV_ILN_23 GBV_ILN_24 GBV_ILN_31 GBV_ILN_32 GBV_ILN_39 GBV_ILN_40 GBV_ILN_62 GBV_ILN_63 GBV_ILN_65 GBV_ILN_69 GBV_ILN_70 GBV_ILN_72 GBV_ILN_73 GBV_ILN_74 GBV_ILN_90 GBV_ILN_95 GBV_ILN_100 GBV_ILN_101 GBV_ILN_105 GBV_ILN_110 GBV_ILN_120 GBV_ILN_138 GBV_ILN_150 GBV_ILN_151 GBV_ILN_161 GBV_ILN_168 GBV_ILN_170 GBV_ILN_171 GBV_ILN_187 GBV_ILN_211 GBV_ILN_213 GBV_ILN_224 GBV_ILN_230 GBV_ILN_252 GBV_ILN_266 GBV_ILN_285 GBV_ILN_293 GBV_ILN_602 GBV_ILN_636 GBV_ILN_702 GBV_ILN_2001 GBV_ILN_2003 GBV_ILN_2004 GBV_ILN_2005 GBV_ILN_2006 GBV_ILN_2007 GBV_ILN_2008 GBV_ILN_2009 GBV_ILN_2010 GBV_ILN_2011 GBV_ILN_2014 GBV_ILN_2015 GBV_ILN_2018 GBV_ILN_2020 GBV_ILN_2021 GBV_ILN_2025 GBV_ILN_2026 GBV_ILN_2027 GBV_ILN_2034 GBV_ILN_2037 GBV_ILN_2038 GBV_ILN_2044 GBV_ILN_2048 GBV_ILN_2049 GBV_ILN_2050 GBV_ILN_2055 GBV_ILN_2056 GBV_ILN_2057 GBV_ILN_2059 GBV_ILN_2061 GBV_ILN_2064 GBV_ILN_2068 GBV_ILN_2088 GBV_ILN_2093 GBV_ILN_2106 GBV_ILN_2108 GBV_ILN_2110 GBV_ILN_2111 GBV_ILN_2113 GBV_ILN_2118 GBV_ILN_2119 GBV_ILN_2122 GBV_ILN_2129 GBV_ILN_2143 GBV_ILN_2144 GBV_ILN_2147 GBV_ILN_2148 GBV_ILN_2152 GBV_ILN_2153 GBV_ILN_2188 GBV_ILN_2190 GBV_ILN_2232 GBV_ILN_2336 GBV_ILN_2470 GBV_ILN_2472 GBV_ILN_2507 GBV_ILN_2522 GBV_ILN_2548 GBV_ILN_4012 GBV_ILN_4029 GBV_ILN_4035 GBV_ILN_4037 GBV_ILN_4046 GBV_ILN_4112 GBV_ILN_4116 GBV_ILN_4125 GBV_ILN_4126 GBV_ILN_4155 GBV_ILN_4242 GBV_ILN_4246 GBV_ILN_4249 GBV_ILN_4251 GBV_ILN_4305 GBV_ILN_4306 GBV_ILN_4307 GBV_ILN_4311 GBV_ILN_4313 GBV_ILN_4314 GBV_ILN_4318 GBV_ILN_4322 GBV_ILN_4323 GBV_ILN_4324 GBV_ILN_4325 GBV_ILN_4326 GBV_ILN_4328 GBV_ILN_4333 GBV_ILN_4334 GBV_ILN_4335 GBV_ILN_4336 GBV_ILN_4338 GBV_ILN_4367 GBV_ILN_4393 GBV_ILN_4598 GBV_ILN_4700 AR 38 2018 2 20 12
allfieldsSound	10.15252/embj.201899916 doi (DE-627)SPR058016554 (SPR)embj.201899916-e DE-627 ger DE-627 rakwb eng Bernardini, Jonathan P verfasserin aut Parkin inhibits BAK and BAX apoptotic function by distinct mechanisms during mitophagy 2018 Text txt rdacontent Computermedien c rdamedia Online-Ressource cr rdacarrier © The Author(s) 2018 Abstract The E3 ubiquitin ligase Parkin is a key effector of the removal of damaged mitochondria by mitophagy. Parkin determines cell fate in response to mitochondrial damage, with its loss promoting early onset Parkinson's disease and potentially also cancer progression. Controlling a cell's apoptotic response is essential to co‐ordinate the removal of damaged mitochondria. We report that following mitochondrial damage‐induced mitophagy, Parkin directly ubiquitinates the apoptotic effector protein BAK at a conserved lysine in its hydrophobic groove, a region that is crucial for BAK activation by BH3‐only proteins and its homo‐dimerisation during apoptosis. Ubiquitination inhibited BAK activity by impairing its activation and the formation of lethal BAK oligomers. Parkin also suppresses BAX‐mediated apoptosis, but in the absence of BAX ubiquitination suggesting an indirect mechanism. In addition, we find that BAK‐dependent mitochondrial outer membrane permeabilisation during apoptosis promotes PINK1‐dependent Parkin activation. Hence, we propose that Parkin directly inhibits BAK to suppress errant apoptosis, thereby allowing the effective clearance of damaged mitochondria, but also promotes clearance of apoptotic mitochondria to limit their potential pro‐inflammatory effect. Synopsis The ubiquitin ligase Parkin plays a protective role in neurodegenerative disease by removing damaged mitochondria and preventing apoptosis, and by limiting the functions of pro‐apoptotic effector proteins BAK and BAX. Defective control of apoptosis may contribute to the pathogenesis of early onset Parkinson's Disease caused by Parkin mutations. Parkin activity is induced by mitochondrial damage during apoptosis.Parkin mono‐ and di‐ubiquitinates BAK at a conserved lysine in its hydrophobic groove.Ubiquitination reduces BAK oligomerisation and apoptotic activity on mitochondria.Parkin prevents BAX mitochondrial localisation and apoptotic activity independent of ubiquitination.Certain Parkinson's Disease‐associated Parkin mutants cannot ubiquitinate BAK and restrain it on mitochondria. Graphical Abstract Autophagic clearance of damaged mitochondria and suppression of apoptotic effector proteins are coordinated functions of the Parkin ubiquitin ligase that are lost upon Parkinson's Disease‐associated mutations. apoptosis (dpeaa)DE-He213 BAK (dpeaa)DE-He213 BAX (dpeaa)DE-He213 mitophagy (dpeaa)DE-He213 Parkin (dpeaa)DE-He213 Brouwer, Jason M verfasserin aut Tan, Iris KL verfasserin aut Sandow, Jarrod J verfasserin aut Huang, Shuai verfasserin aut Stafford, Che A verfasserin aut Bankovacki, Aleksandra verfasserin aut Riffkin, Christopher D verfasserin aut Wardak, Ahmad Z verfasserin aut Czabotar, Peter E verfasserin aut Lazarou, Michael verfasserin (orcid)0000-0003-2150-5545 aut Dewson, Grant verfasserin (orcid)0000-0003-4251-8898 aut Enthalten in The EMBO Journal Nature Publishing Group UK, 2023 38(2018), 2 vom: 20. Dez. (DE-627)266022529 (DE-600)1467419-1 1460-2075 nnns volume:38 year:2018 number:2 day:20 month:12 https://dx.doi.org/10.15252/embj.201899916 X:SPRINGER Resolving-System lizenzpflichtig Volltext SYSFLAG_0 GBV_SPRINGER GBV_ILN_20 GBV_ILN_22 GBV_ILN_23 GBV_ILN_24 GBV_ILN_31 GBV_ILN_32 GBV_ILN_39 GBV_ILN_40 GBV_ILN_62 GBV_ILN_63 GBV_ILN_65 GBV_ILN_69 GBV_ILN_70 GBV_ILN_72 GBV_ILN_73 GBV_ILN_74 GBV_ILN_90 GBV_ILN_95 GBV_ILN_100 GBV_ILN_101 GBV_ILN_105 GBV_ILN_110 GBV_ILN_120 GBV_ILN_138 GBV_ILN_150 GBV_ILN_151 GBV_ILN_161 GBV_ILN_168 GBV_ILN_170 GBV_ILN_171 GBV_ILN_187 GBV_ILN_211 GBV_ILN_213 GBV_ILN_224 GBV_ILN_230 GBV_ILN_252 GBV_ILN_266 GBV_ILN_285 GBV_ILN_293 GBV_ILN_602 GBV_ILN_636 GBV_ILN_702 GBV_ILN_2001 GBV_ILN_2003 GBV_ILN_2004 GBV_ILN_2005 GBV_ILN_2006 GBV_ILN_2007 GBV_ILN_2008 GBV_ILN_2009 GBV_ILN_2010 GBV_ILN_2011 GBV_ILN_2014 GBV_ILN_2015 GBV_ILN_2018 GBV_ILN_2020 GBV_ILN_2021 GBV_ILN_2025 GBV_ILN_2026 GBV_ILN_2027 GBV_ILN_2034 GBV_ILN_2037 GBV_ILN_2038 GBV_ILN_2044 GBV_ILN_2048 GBV_ILN_2049 GBV_ILN_2050 GBV_ILN_2055 GBV_ILN_2056 GBV_ILN_2057 GBV_ILN_2059 GBV_ILN_2061 GBV_ILN_2064 GBV_ILN_2068 GBV_ILN_2088 GBV_ILN_2093 GBV_ILN_2106 GBV_ILN_2108 GBV_ILN_2110 GBV_ILN_2111 GBV_ILN_2113 GBV_ILN_2118 GBV_ILN_2119 GBV_ILN_2122 GBV_ILN_2129 GBV_ILN_2143 GBV_ILN_2144 GBV_ILN_2147 GBV_ILN_2148 GBV_ILN_2152 GBV_ILN_2153 GBV_ILN_2188 GBV_ILN_2190 GBV_ILN_2232 GBV_ILN_2336 GBV_ILN_2470 GBV_ILN_2472 GBV_ILN_2507 GBV_ILN_2522 GBV_ILN_2548 GBV_ILN_4012 GBV_ILN_4029 GBV_ILN_4035 GBV_ILN_4037 GBV_ILN_4046 GBV_ILN_4112 GBV_ILN_4116 GBV_ILN_4125 GBV_ILN_4126 GBV_ILN_4155 GBV_ILN_4242 GBV_ILN_4246 GBV_ILN_4249 GBV_ILN_4251 GBV_ILN_4305 GBV_ILN_4306 GBV_ILN_4307 GBV_ILN_4311 GBV_ILN_4313 GBV_ILN_4314 GBV_ILN_4318 GBV_ILN_4322 GBV_ILN_4323 GBV_ILN_4324 GBV_ILN_4325 GBV_ILN_4326 GBV_ILN_4328 GBV_ILN_4333 GBV_ILN_4334 GBV_ILN_4335 GBV_ILN_4336 GBV_ILN_4338 GBV_ILN_4367 GBV_ILN_4393 GBV_ILN_4598 GBV_ILN_4700 AR 38 2018 2 20 12
language	English
source	Enthalten in The EMBO Journal 38(2018), 2 vom: 20. Dez. volume:38 year:2018 number:2 day:20 month:12
sourceStr	Enthalten in The EMBO Journal 38(2018), 2 vom: 20. Dez. volume:38 year:2018 number:2 day:20 month:12
format_phy_str_mv	Article
institution	findex.gbv.de
topic_facet	apoptosis BAK BAX mitophagy Parkin
isfreeaccess_bool	false
container_title	The EMBO Journal
authorswithroles_txt_mv	Bernardini, Jonathan P @@aut@@ Brouwer, Jason M @@aut@@ Tan, Iris KL @@aut@@ Sandow, Jarrod J @@aut@@ Huang, Shuai @@aut@@ Stafford, Che A @@aut@@ Bankovacki, Aleksandra @@aut@@ Riffkin, Christopher D @@aut@@ Wardak, Ahmad Z @@aut@@ Czabotar, Peter E @@aut@@ Lazarou, Michael @@aut@@ Dewson, Grant @@aut@@
publishDateDaySort_date	2018-12-20T00:00:00Z
hierarchy_top_id	266022529
id	SPR058016554
language_de	englisch
fullrecord	<?xml version="1.0" encoding="UTF-8"?><collection xmlns="http://www.loc.gov/MARC21/slim"><record><leader>01000naa a22002652 4500</leader><controlfield tag="001">SPR058016554</controlfield><controlfield tag="003">DE-627</controlfield><controlfield tag="005">20241024065139.0</controlfield><controlfield tag="007">cr uuu---uuuuu</controlfield><controlfield tag="008">241024s2018 xx \|\|\|\|\|o 00\| \|\|eng c</controlfield><datafield tag="024" ind1="7" ind2=" "><subfield code="a">10.15252/embj.201899916</subfield><subfield code="2">doi</subfield></datafield><datafield tag="035" ind1=" " ind2=" "><subfield code="a">(DE-627)SPR058016554</subfield></datafield><datafield tag="035" ind1=" " ind2=" "><subfield code="a">(SPR)embj.201899916-e</subfield></datafield><datafield tag="040" ind1=" " ind2=" "><subfield code="a">DE-627</subfield><subfield code="b">ger</subfield><subfield code="c">DE-627</subfield><subfield code="e">rakwb</subfield></datafield><datafield tag="041" ind1=" " ind2=" "><subfield code="a">eng</subfield></datafield><datafield tag="100" ind1="1" ind2=" "><subfield code="a">Bernardini, Jonathan P</subfield><subfield code="e">verfasserin</subfield><subfield code="4">aut</subfield></datafield><datafield tag="245" ind1="1" ind2="0"><subfield code="a">Parkin inhibits BAK and BAX apoptotic function by distinct mechanisms during mitophagy</subfield></datafield><datafield tag="264" ind1=" " ind2="1"><subfield code="c">2018</subfield></datafield><datafield tag="336" ind1=" " ind2=" "><subfield code="a">Text</subfield><subfield code="b">txt</subfield><subfield code="2">rdacontent</subfield></datafield><datafield tag="337" ind1=" " ind2=" "><subfield code="a">Computermedien</subfield><subfield code="b">c</subfield><subfield code="2">rdamedia</subfield></datafield><datafield tag="338" ind1=" " ind2=" "><subfield code="a">Online-Ressource</subfield><subfield code="b">cr</subfield><subfield code="2">rdacarrier</subfield></datafield><datafield tag="500" ind1=" " ind2=" "><subfield code="a">© The Author(s) 2018</subfield></datafield><datafield tag="520" ind1=" " ind2=" "><subfield code="a">Abstract The E3 ubiquitin ligase Parkin is a key effector of the removal of damaged mitochondria by mitophagy. Parkin determines cell fate in response to mitochondrial damage, with its loss promoting early onset Parkinson's disease and potentially also cancer progression. Controlling a cell's apoptotic response is essential to co‐ordinate the removal of damaged mitochondria. We report that following mitochondrial damage‐induced mitophagy, Parkin directly ubiquitinates the apoptotic effector protein BAK at a conserved lysine in its hydrophobic groove, a region that is crucial for BAK activation by BH3‐only proteins and its homo‐dimerisation during apoptosis. Ubiquitination inhibited BAK activity by impairing its activation and the formation of lethal BAK oligomers. Parkin also suppresses BAX‐mediated apoptosis, but in the absence of BAX ubiquitination suggesting an indirect mechanism. In addition, we find that BAK‐dependent mitochondrial outer membrane permeabilisation during apoptosis promotes PINK1‐dependent Parkin activation. Hence, we propose that Parkin directly inhibits BAK to suppress errant apoptosis, thereby allowing the effective clearance of damaged mitochondria, but also promotes clearance of apoptotic mitochondria to limit their potential pro‐inflammatory effect.</subfield></datafield><datafield tag="520" ind1=" " ind2=" "><subfield code="a">Synopsis The ubiquitin ligase Parkin plays a protective role in neurodegenerative disease by removing damaged mitochondria and preventing apoptosis, and by limiting the functions of pro‐apoptotic effector proteins BAK and BAX. Defective control of apoptosis may contribute to the pathogenesis of early onset Parkinson's Disease caused by Parkin mutations. Parkin activity is induced by mitochondrial damage during apoptosis.Parkin mono‐ and di‐ubiquitinates BAK at a conserved lysine in its hydrophobic groove.Ubiquitination reduces BAK oligomerisation and apoptotic activity on mitochondria.Parkin prevents BAX mitochondrial localisation and apoptotic activity independent of ubiquitination.Certain Parkinson's Disease‐associated Parkin mutants cannot ubiquitinate BAK and restrain it on mitochondria.</subfield></datafield><datafield tag="520" ind1=" " ind2=" "><subfield code="a">Graphical Abstract Autophagic clearance of damaged mitochondria and suppression of apoptotic effector proteins are coordinated functions of the Parkin ubiquitin ligase that are lost upon Parkinson's Disease‐associated mutations.</subfield></datafield><datafield tag="650" ind1=" " ind2="4"><subfield code="a">apoptosis</subfield><subfield code="7">(dpeaa)DE-He213</subfield></datafield><datafield tag="650" ind1=" " ind2="4"><subfield code="a">BAK</subfield><subfield code="7">(dpeaa)DE-He213</subfield></datafield><datafield tag="650" ind1=" " ind2="4"><subfield code="a">BAX</subfield><subfield code="7">(dpeaa)DE-He213</subfield></datafield><datafield tag="650" ind1=" " ind2="4"><subfield code="a">mitophagy</subfield><subfield code="7">(dpeaa)DE-He213</subfield></datafield><datafield tag="650" ind1=" " ind2="4"><subfield code="a">Parkin</subfield><subfield code="7">(dpeaa)DE-He213</subfield></datafield><datafield tag="700" ind1="1" ind2=" "><subfield code="a">Brouwer, Jason M</subfield><subfield code="e">verfasserin</subfield><subfield code="4">aut</subfield></datafield><datafield tag="700" ind1="1" ind2=" "><subfield code="a">Tan, Iris KL</subfield><subfield code="e">verfasserin</subfield><subfield code="4">aut</subfield></datafield><datafield tag="700" ind1="1" ind2=" "><subfield code="a">Sandow, Jarrod J</subfield><subfield code="e">verfasserin</subfield><subfield code="4">aut</subfield></datafield><datafield tag="700" ind1="1" ind2=" "><subfield code="a">Huang, Shuai</subfield><subfield code="e">verfasserin</subfield><subfield code="4">aut</subfield></datafield><datafield tag="700" ind1="1" ind2=" "><subfield code="a">Stafford, Che A</subfield><subfield code="e">verfasserin</subfield><subfield code="4">aut</subfield></datafield><datafield tag="700" ind1="1" ind2=" "><subfield code="a">Bankovacki, Aleksandra</subfield><subfield code="e">verfasserin</subfield><subfield code="4">aut</subfield></datafield><datafield tag="700" ind1="1" ind2=" "><subfield code="a">Riffkin, Christopher D</subfield><subfield code="e">verfasserin</subfield><subfield code="4">aut</subfield></datafield><datafield tag="700" ind1="1" ind2=" "><subfield code="a">Wardak, Ahmad Z</subfield><subfield code="e">verfasserin</subfield><subfield code="4">aut</subfield></datafield><datafield tag="700" ind1="1" ind2=" "><subfield code="a">Czabotar, Peter E</subfield><subfield code="e">verfasserin</subfield><subfield code="4">aut</subfield></datafield><datafield tag="700" ind1="1" ind2=" "><subfield code="a">Lazarou, Michael</subfield><subfield code="e">verfasserin</subfield><subfield code="0">(orcid)0000-0003-2150-5545</subfield><subfield code="4">aut</subfield></datafield><datafield tag="700" ind1="1" ind2=" "><subfield code="a">Dewson, Grant</subfield><subfield code="e">verfasserin</subfield><subfield code="0">(orcid)0000-0003-4251-8898</subfield><subfield code="4">aut</subfield></datafield><datafield tag="773" ind1="0" ind2="8"><subfield code="i">Enthalten in</subfield><subfield code="t">The EMBO Journal</subfield><subfield code="d">Nature Publishing Group UK, 2023</subfield><subfield code="g">38(2018), 2 vom: 20. 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author	Bernardini, Jonathan P
spellingShingle	Bernardini, Jonathan P misc apoptosis misc BAK misc BAX misc mitophagy misc Parkin Parkin inhibits BAK and BAX apoptotic function by distinct mechanisms during mitophagy
authorStr	Bernardini, Jonathan P
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topic_title	Parkin inhibits BAK and BAX apoptotic function by distinct mechanisms during mitophagy apoptosis (dpeaa)DE-He213 BAK (dpeaa)DE-He213 BAX (dpeaa)DE-He213 mitophagy (dpeaa)DE-He213 Parkin (dpeaa)DE-He213
topic	misc apoptosis misc BAK misc BAX misc mitophagy misc Parkin
topic_unstemmed	misc apoptosis misc BAK misc BAX misc mitophagy misc Parkin
topic_browse	misc apoptosis misc BAK misc BAX misc mitophagy misc Parkin
format_facet	Elektronische Aufsätze Aufsätze Elektronische Ressource
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title	Parkin inhibits BAK and BAX apoptotic function by distinct mechanisms during mitophagy
ctrlnum	(DE-627)SPR058016554 (SPR)embj.201899916-e
title_full	Parkin inhibits BAK and BAX apoptotic function by distinct mechanisms during mitophagy
author_sort	Bernardini, Jonathan P
journal	The EMBO Journal
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author_browse	Bernardini, Jonathan P Brouwer, Jason M Tan, Iris KL Sandow, Jarrod J Huang, Shuai Stafford, Che A Bankovacki, Aleksandra Riffkin, Christopher D Wardak, Ahmad Z Czabotar, Peter E Lazarou, Michael Dewson, Grant
container_volume	38
format_se	Elektronische Aufsätze
author-letter	Bernardini, Jonathan P
doi_str_mv	10.15252/embj.201899916
normlink	(ORCID)0000-0003-2150-5545 (ORCID)0000-0003-4251-8898
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title_sort	parkin inhibits bak and bax apoptotic function by distinct mechanisms during mitophagy
title_auth	Parkin inhibits BAK and BAX apoptotic function by distinct mechanisms during mitophagy
abstract	Abstract The E3 ubiquitin ligase Parkin is a key effector of the removal of damaged mitochondria by mitophagy. Parkin determines cell fate in response to mitochondrial damage, with its loss promoting early onset Parkinson's disease and potentially also cancer progression. Controlling a cell's apoptotic response is essential to co‐ordinate the removal of damaged mitochondria. We report that following mitochondrial damage‐induced mitophagy, Parkin directly ubiquitinates the apoptotic effector protein BAK at a conserved lysine in its hydrophobic groove, a region that is crucial for BAK activation by BH3‐only proteins and its homo‐dimerisation during apoptosis. Ubiquitination inhibited BAK activity by impairing its activation and the formation of lethal BAK oligomers. Parkin also suppresses BAX‐mediated apoptosis, but in the absence of BAX ubiquitination suggesting an indirect mechanism. In addition, we find that BAK‐dependent mitochondrial outer membrane permeabilisation during apoptosis promotes PINK1‐dependent Parkin activation. Hence, we propose that Parkin directly inhibits BAK to suppress errant apoptosis, thereby allowing the effective clearance of damaged mitochondria, but also promotes clearance of apoptotic mitochondria to limit their potential pro‐inflammatory effect. Synopsis The ubiquitin ligase Parkin plays a protective role in neurodegenerative disease by removing damaged mitochondria and preventing apoptosis, and by limiting the functions of pro‐apoptotic effector proteins BAK and BAX. Defective control of apoptosis may contribute to the pathogenesis of early onset Parkinson's Disease caused by Parkin mutations. Parkin activity is induced by mitochondrial damage during apoptosis.Parkin mono‐ and di‐ubiquitinates BAK at a conserved lysine in its hydrophobic groove.Ubiquitination reduces BAK oligomerisation and apoptotic activity on mitochondria.Parkin prevents BAX mitochondrial localisation and apoptotic activity independent of ubiquitination.Certain Parkinson's Disease‐associated Parkin mutants cannot ubiquitinate BAK and restrain it on mitochondria. Graphical Abstract Autophagic clearance of damaged mitochondria and suppression of apoptotic effector proteins are coordinated functions of the Parkin ubiquitin ligase that are lost upon Parkinson's Disease‐associated mutations. © The Author(s) 2018
abstractGer	Abstract The E3 ubiquitin ligase Parkin is a key effector of the removal of damaged mitochondria by mitophagy. Parkin determines cell fate in response to mitochondrial damage, with its loss promoting early onset Parkinson's disease and potentially also cancer progression. Controlling a cell's apoptotic response is essential to co‐ordinate the removal of damaged mitochondria. We report that following mitochondrial damage‐induced mitophagy, Parkin directly ubiquitinates the apoptotic effector protein BAK at a conserved lysine in its hydrophobic groove, a region that is crucial for BAK activation by BH3‐only proteins and its homo‐dimerisation during apoptosis. Ubiquitination inhibited BAK activity by impairing its activation and the formation of lethal BAK oligomers. Parkin also suppresses BAX‐mediated apoptosis, but in the absence of BAX ubiquitination suggesting an indirect mechanism. In addition, we find that BAK‐dependent mitochondrial outer membrane permeabilisation during apoptosis promotes PINK1‐dependent Parkin activation. Hence, we propose that Parkin directly inhibits BAK to suppress errant apoptosis, thereby allowing the effective clearance of damaged mitochondria, but also promotes clearance of apoptotic mitochondria to limit their potential pro‐inflammatory effect. Synopsis The ubiquitin ligase Parkin plays a protective role in neurodegenerative disease by removing damaged mitochondria and preventing apoptosis, and by limiting the functions of pro‐apoptotic effector proteins BAK and BAX. Defective control of apoptosis may contribute to the pathogenesis of early onset Parkinson's Disease caused by Parkin mutations. Parkin activity is induced by mitochondrial damage during apoptosis.Parkin mono‐ and di‐ubiquitinates BAK at a conserved lysine in its hydrophobic groove.Ubiquitination reduces BAK oligomerisation and apoptotic activity on mitochondria.Parkin prevents BAX mitochondrial localisation and apoptotic activity independent of ubiquitination.Certain Parkinson's Disease‐associated Parkin mutants cannot ubiquitinate BAK and restrain it on mitochondria. Graphical Abstract Autophagic clearance of damaged mitochondria and suppression of apoptotic effector proteins are coordinated functions of the Parkin ubiquitin ligase that are lost upon Parkinson's Disease‐associated mutations. © The Author(s) 2018
abstract_unstemmed	Abstract The E3 ubiquitin ligase Parkin is a key effector of the removal of damaged mitochondria by mitophagy. Parkin determines cell fate in response to mitochondrial damage, with its loss promoting early onset Parkinson's disease and potentially also cancer progression. Controlling a cell's apoptotic response is essential to co‐ordinate the removal of damaged mitochondria. We report that following mitochondrial damage‐induced mitophagy, Parkin directly ubiquitinates the apoptotic effector protein BAK at a conserved lysine in its hydrophobic groove, a region that is crucial for BAK activation by BH3‐only proteins and its homo‐dimerisation during apoptosis. Ubiquitination inhibited BAK activity by impairing its activation and the formation of lethal BAK oligomers. Parkin also suppresses BAX‐mediated apoptosis, but in the absence of BAX ubiquitination suggesting an indirect mechanism. In addition, we find that BAK‐dependent mitochondrial outer membrane permeabilisation during apoptosis promotes PINK1‐dependent Parkin activation. Hence, we propose that Parkin directly inhibits BAK to suppress errant apoptosis, thereby allowing the effective clearance of damaged mitochondria, but also promotes clearance of apoptotic mitochondria to limit their potential pro‐inflammatory effect. Synopsis The ubiquitin ligase Parkin plays a protective role in neurodegenerative disease by removing damaged mitochondria and preventing apoptosis, and by limiting the functions of pro‐apoptotic effector proteins BAK and BAX. Defective control of apoptosis may contribute to the pathogenesis of early onset Parkinson's Disease caused by Parkin mutations. Parkin activity is induced by mitochondrial damage during apoptosis.Parkin mono‐ and di‐ubiquitinates BAK at a conserved lysine in its hydrophobic groove.Ubiquitination reduces BAK oligomerisation and apoptotic activity on mitochondria.Parkin prevents BAX mitochondrial localisation and apoptotic activity independent of ubiquitination.Certain Parkinson's Disease‐associated Parkin mutants cannot ubiquitinate BAK and restrain it on mitochondria. Graphical Abstract Autophagic clearance of damaged mitochondria and suppression of apoptotic effector proteins are coordinated functions of the Parkin ubiquitin ligase that are lost upon Parkinson's Disease‐associated mutations. © The Author(s) 2018
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container_issue	2
title_short	Parkin inhibits BAK and BAX apoptotic function by distinct mechanisms during mitophagy
url	https://dx.doi.org/10.15252/embj.201899916
remote_bool	true
author2	Brouwer, Jason M Tan, Iris KL Sandow, Jarrod J Huang, Shuai Stafford, Che A Bankovacki, Aleksandra Riffkin, Christopher D Wardak, Ahmad Z Czabotar, Peter E Lazarou, Michael Dewson, Grant
author2Str	Brouwer, Jason M Tan, Iris KL Sandow, Jarrod J Huang, Shuai Stafford, Che A Bankovacki, Aleksandra Riffkin, Christopher D Wardak, Ahmad Z Czabotar, Peter E Lazarou, Michael Dewson, Grant
ppnlink	266022529
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isOA_txt	false
hochschulschrift_bool	false
doi_str	10.15252/embj.201899916
up_date	2024-10-24T04:56:33.804Z
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Parkin inhibits BAK and BAX apoptotic function by distinct mechanisms during mitophagy

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