Phosphatidylinositol 4,5‐bisphosphate controls Rab7 and PLEKHM1 membrane cycling during autophagosome–lysosome fusion

Abstract The small GTPase Rab7 is a key organizer of receptor sorting and lysosomal degradation by recruiting of a variety of effectors depending on its GDP/GTP‐bound state. However, molecular mechanisms that trigger Rab7 inactivation remain elusive. Here we find that, among the endosomal pools, Rab...
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Autor*in:	Baba, Takashi [verfasserIn] Toth, Daniel J [verfasserIn] Sengupta, Nivedita [verfasserIn] Kim, Yeun Ju [verfasserIn] Balla, Tamas [verfasserIn]

Format:	E-Artikel
Sprache:	Englisch

Erschienen:	2019

Schlagwörter:	autophagy lysosome phosphatidylinositol 4‐kinase phosphoinositide Rab7

Anmerkung:	© This article is a U.S. Government work and is in the public domain in the USA 2019

Übergeordnetes Werk:	Enthalten in: The EMBO Journal - Nature Publishing Group UK, 2023, 38(2019), 8 vom: 13. März
Übergeordnetes Werk:	volume:38 ; year:2019 ; number:8 ; day:13 ; month:03

Links:	Volltext

DOI / URN:	10.15252/embj.2018100312

Katalog-ID:	SPR058017569

Internformat


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520			\|a Abstract The small GTPase Rab7 is a key organizer of receptor sorting and lysosomal degradation by recruiting of a variety of effectors depending on its GDP/GTP‐bound state. However, molecular mechanisms that trigger Rab7 inactivation remain elusive. Here we find that, among the endosomal pools, Rab7‐positive compartments possess the highest level of PI4P, which is primarily produced by PI4K2A kinase. Acute conversion of this endosomal PI4P to PI(4,5)$ P_{2} $ causes Rab7 dissociation from late endosomes and releases a regulator of autophagosome–lysosome fusion, PLEKHM1, from the membrane. Rab7 effectors Vps35 and RILP are not affected by acute PI(4,5)$ P_{2} $ production. Deletion of PI4K2A greatly reduces PIP5Kγ‐mediated PI(4,5)$ P_{2} $ production in Rab7‐positive endosomes leading to impaired Rab7 inactivation and increased number of LC3‐positive structures with defective autophagosome–lysosome fusion. These results reveal a late endosomal PI4P‐PI(4,5)$ P_{2} $‐dependent regulatory loop that impacts autophagosome flux by affecting Rab7 cycling and PLEKHM1 association.
520			\|a Synopsis Phosphoinositides are key regulators of small GTP‐binding proteins, but how they control the activity of Rab GTPases is poorly understood. PI4K2A and PIP5Kγ act sequentially to generate PI(4,5)$ P_{2} $, which promotes membrane fusion during autophagy through Rab7 inactivation and PLEKHM1 release from late endosomes. PI4K2A is key for PI4P production in Rab7‐positive endosomes.PIP5Kγ converts PI4P to PI(4,5)$ P_{2} $ at late endosomes to inactivate Rab7.PI4K2A or PIP5Kγ depletion impairs acidification of autophagosomes.The conversion of PI4P to PI(4,5)$ P_{2} $ promotes the release of PLEKHM1 from late endosome.
520			\|a Graphical Abstract PI4K2A and PIP5Kγ act sequentially to generate PI(4,5)$ P_{2} $, which promotes membrane fusion during autophagy through Rab7 inactivation and PLEKHM1 release from late endosomes.
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700	1		\|a Balla, Tamas \|e verfasserin \|0 (orcid)0000-0002-9077-3335 \|4 aut
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912			\|a GBV_ILN_161
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912			\|a GBV_ILN_187
912			\|a GBV_ILN_211
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912			\|a GBV_ILN_2055
912			\|a GBV_ILN_2056
912			\|a GBV_ILN_2057
912			\|a GBV_ILN_2059
912			\|a GBV_ILN_2061
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912			\|a GBV_ILN_2068
912			\|a GBV_ILN_2088
912			\|a GBV_ILN_2093
912			\|a GBV_ILN_2106
912			\|a GBV_ILN_2108
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912			\|a GBV_ILN_4326
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Indexfelder

author_variant	t b tb d j t dj djt n s ns y j k yj yjk t b tb
matchkey_str	article:14602075:2019----::hshtdlnstl5ipopaeotosa7npeh1ebaeylndrna
hierarchy_sort_str	2019
publishDate	2019
allfields	10.15252/embj.2018100312 doi (DE-627)SPR058017569 (SPR)embj.2018100312-e DE-627 ger DE-627 rakwb eng Baba, Takashi verfasserin (orcid)0000-0003-4131-7306 aut Phosphatidylinositol 4,5‐bisphosphate controls Rab7 and PLEKHM1 membrane cycling during autophagosome–lysosome fusion 2019 Text txt rdacontent Computermedien c rdamedia Online-Ressource cr rdacarrier © This article is a U.S. Government work and is in the public domain in the USA 2019 Abstract The small GTPase Rab7 is a key organizer of receptor sorting and lysosomal degradation by recruiting of a variety of effectors depending on its GDP/GTP‐bound state. However, molecular mechanisms that trigger Rab7 inactivation remain elusive. Here we find that, among the endosomal pools, Rab7‐positive compartments possess the highest level of PI4P, which is primarily produced by PI4K2A kinase. Acute conversion of this endosomal PI4P to PI(4,5)$ P_{2} $ causes Rab7 dissociation from late endosomes and releases a regulator of autophagosome–lysosome fusion, PLEKHM1, from the membrane. Rab7 effectors Vps35 and RILP are not affected by acute PI(4,5)$ P_{2} $ production. Deletion of PI4K2A greatly reduces PIP5Kγ‐mediated PI(4,5)$ P_{2} $ production in Rab7‐positive endosomes leading to impaired Rab7 inactivation and increased number of LC3‐positive structures with defective autophagosome–lysosome fusion. These results reveal a late endosomal PI4P‐PI(4,5)$ P_{2} $‐dependent regulatory loop that impacts autophagosome flux by affecting Rab7 cycling and PLEKHM1 association. Synopsis Phosphoinositides are key regulators of small GTP‐binding proteins, but how they control the activity of Rab GTPases is poorly understood. PI4K2A and PIP5Kγ act sequentially to generate PI(4,5)$ P_{2} $, which promotes membrane fusion during autophagy through Rab7 inactivation and PLEKHM1 release from late endosomes. PI4K2A is key for PI4P production in Rab7‐positive endosomes.PIP5Kγ converts PI4P to PI(4,5)$ P_{2} $ at late endosomes to inactivate Rab7.PI4K2A or PIP5Kγ depletion impairs acidification of autophagosomes.The conversion of PI4P to PI(4,5)$ P_{2} $ promotes the release of PLEKHM1 from late endosome. Graphical Abstract PI4K2A and PIP5Kγ act sequentially to generate PI(4,5)$ P_{2} $, which promotes membrane fusion during autophagy through Rab7 inactivation and PLEKHM1 release from late endosomes. autophagy (dpeaa)DE-He213 lysosome (dpeaa)DE-He213 phosphatidylinositol 4‐kinase (dpeaa)DE-He213 phosphoinositide (dpeaa)DE-He213 Rab7 (dpeaa)DE-He213 Toth, Daniel J verfasserin aut Sengupta, Nivedita verfasserin aut Kim, Yeun Ju verfasserin aut Balla, Tamas verfasserin (orcid)0000-0002-9077-3335 aut Enthalten in The EMBO Journal Nature Publishing Group UK, 2023 38(2019), 8 vom: 13. März (DE-627)266022529 (DE-600)1467419-1 1460-2075 nnns volume:38 year:2019 number:8 day:13 month:03 https://dx.doi.org/10.15252/embj.2018100312 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_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_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 2019 8 13 03
spelling	10.15252/embj.2018100312 doi (DE-627)SPR058017569 (SPR)embj.2018100312-e DE-627 ger DE-627 rakwb eng Baba, Takashi verfasserin (orcid)0000-0003-4131-7306 aut Phosphatidylinositol 4,5‐bisphosphate controls Rab7 and PLEKHM1 membrane cycling during autophagosome–lysosome fusion 2019 Text txt rdacontent Computermedien c rdamedia Online-Ressource cr rdacarrier © This article is a U.S. Government work and is in the public domain in the USA 2019 Abstract The small GTPase Rab7 is a key organizer of receptor sorting and lysosomal degradation by recruiting of a variety of effectors depending on its GDP/GTP‐bound state. However, molecular mechanisms that trigger Rab7 inactivation remain elusive. Here we find that, among the endosomal pools, Rab7‐positive compartments possess the highest level of PI4P, which is primarily produced by PI4K2A kinase. Acute conversion of this endosomal PI4P to PI(4,5)$ P_{2} $ causes Rab7 dissociation from late endosomes and releases a regulator of autophagosome–lysosome fusion, PLEKHM1, from the membrane. Rab7 effectors Vps35 and RILP are not affected by acute PI(4,5)$ P_{2} $ production. Deletion of PI4K2A greatly reduces PIP5Kγ‐mediated PI(4,5)$ P_{2} $ production in Rab7‐positive endosomes leading to impaired Rab7 inactivation and increased number of LC3‐positive structures with defective autophagosome–lysosome fusion. These results reveal a late endosomal PI4P‐PI(4,5)$ P_{2} $‐dependent regulatory loop that impacts autophagosome flux by affecting Rab7 cycling and PLEKHM1 association. Synopsis Phosphoinositides are key regulators of small GTP‐binding proteins, but how they control the activity of Rab GTPases is poorly understood. PI4K2A and PIP5Kγ act sequentially to generate PI(4,5)$ P_{2} $, which promotes membrane fusion during autophagy through Rab7 inactivation and PLEKHM1 release from late endosomes. PI4K2A is key for PI4P production in Rab7‐positive endosomes.PIP5Kγ converts PI4P to PI(4,5)$ P_{2} $ at late endosomes to inactivate Rab7.PI4K2A or PIP5Kγ depletion impairs acidification of autophagosomes.The conversion of PI4P to PI(4,5)$ P_{2} $ promotes the release of PLEKHM1 from late endosome. Graphical Abstract PI4K2A and PIP5Kγ act sequentially to generate PI(4,5)$ P_{2} $, which promotes membrane fusion during autophagy through Rab7 inactivation and PLEKHM1 release from late endosomes. autophagy (dpeaa)DE-He213 lysosome (dpeaa)DE-He213 phosphatidylinositol 4‐kinase (dpeaa)DE-He213 phosphoinositide (dpeaa)DE-He213 Rab7 (dpeaa)DE-He213 Toth, Daniel J verfasserin aut Sengupta, Nivedita verfasserin aut Kim, Yeun Ju verfasserin aut Balla, Tamas verfasserin (orcid)0000-0002-9077-3335 aut Enthalten in The EMBO Journal Nature Publishing Group UK, 2023 38(2019), 8 vom: 13. März (DE-627)266022529 (DE-600)1467419-1 1460-2075 nnns volume:38 year:2019 number:8 day:13 month:03 https://dx.doi.org/10.15252/embj.2018100312 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_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_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 2019 8 13 03
allfields_unstemmed	10.15252/embj.2018100312 doi (DE-627)SPR058017569 (SPR)embj.2018100312-e DE-627 ger DE-627 rakwb eng Baba, Takashi verfasserin (orcid)0000-0003-4131-7306 aut Phosphatidylinositol 4,5‐bisphosphate controls Rab7 and PLEKHM1 membrane cycling during autophagosome–lysosome fusion 2019 Text txt rdacontent Computermedien c rdamedia Online-Ressource cr rdacarrier © This article is a U.S. Government work and is in the public domain in the USA 2019 Abstract The small GTPase Rab7 is a key organizer of receptor sorting and lysosomal degradation by recruiting of a variety of effectors depending on its GDP/GTP‐bound state. However, molecular mechanisms that trigger Rab7 inactivation remain elusive. Here we find that, among the endosomal pools, Rab7‐positive compartments possess the highest level of PI4P, which is primarily produced by PI4K2A kinase. Acute conversion of this endosomal PI4P to PI(4,5)$ P_{2} $ causes Rab7 dissociation from late endosomes and releases a regulator of autophagosome–lysosome fusion, PLEKHM1, from the membrane. Rab7 effectors Vps35 and RILP are not affected by acute PI(4,5)$ P_{2} $ production. Deletion of PI4K2A greatly reduces PIP5Kγ‐mediated PI(4,5)$ P_{2} $ production in Rab7‐positive endosomes leading to impaired Rab7 inactivation and increased number of LC3‐positive structures with defective autophagosome–lysosome fusion. These results reveal a late endosomal PI4P‐PI(4,5)$ P_{2} $‐dependent regulatory loop that impacts autophagosome flux by affecting Rab7 cycling and PLEKHM1 association. Synopsis Phosphoinositides are key regulators of small GTP‐binding proteins, but how they control the activity of Rab GTPases is poorly understood. PI4K2A and PIP5Kγ act sequentially to generate PI(4,5)$ P_{2} $, which promotes membrane fusion during autophagy through Rab7 inactivation and PLEKHM1 release from late endosomes. PI4K2A is key for PI4P production in Rab7‐positive endosomes.PIP5Kγ converts PI4P to PI(4,5)$ P_{2} $ at late endosomes to inactivate Rab7.PI4K2A or PIP5Kγ depletion impairs acidification of autophagosomes.The conversion of PI4P to PI(4,5)$ P_{2} $ promotes the release of PLEKHM1 from late endosome. Graphical Abstract PI4K2A and PIP5Kγ act sequentially to generate PI(4,5)$ P_{2} $, which promotes membrane fusion during autophagy through Rab7 inactivation and PLEKHM1 release from late endosomes. autophagy (dpeaa)DE-He213 lysosome (dpeaa)DE-He213 phosphatidylinositol 4‐kinase (dpeaa)DE-He213 phosphoinositide (dpeaa)DE-He213 Rab7 (dpeaa)DE-He213 Toth, Daniel J verfasserin aut Sengupta, Nivedita verfasserin aut Kim, Yeun Ju verfasserin aut Balla, Tamas verfasserin (orcid)0000-0002-9077-3335 aut Enthalten in The EMBO Journal Nature Publishing Group UK, 2023 38(2019), 8 vom: 13. März (DE-627)266022529 (DE-600)1467419-1 1460-2075 nnns volume:38 year:2019 number:8 day:13 month:03 https://dx.doi.org/10.15252/embj.2018100312 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_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_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 2019 8 13 03
allfieldsGer	10.15252/embj.2018100312 doi (DE-627)SPR058017569 (SPR)embj.2018100312-e DE-627 ger DE-627 rakwb eng Baba, Takashi verfasserin (orcid)0000-0003-4131-7306 aut Phosphatidylinositol 4,5‐bisphosphate controls Rab7 and PLEKHM1 membrane cycling during autophagosome–lysosome fusion 2019 Text txt rdacontent Computermedien c rdamedia Online-Ressource cr rdacarrier © This article is a U.S. Government work and is in the public domain in the USA 2019 Abstract The small GTPase Rab7 is a key organizer of receptor sorting and lysosomal degradation by recruiting of a variety of effectors depending on its GDP/GTP‐bound state. However, molecular mechanisms that trigger Rab7 inactivation remain elusive. Here we find that, among the endosomal pools, Rab7‐positive compartments possess the highest level of PI4P, which is primarily produced by PI4K2A kinase. Acute conversion of this endosomal PI4P to PI(4,5)$ P_{2} $ causes Rab7 dissociation from late endosomes and releases a regulator of autophagosome–lysosome fusion, PLEKHM1, from the membrane. Rab7 effectors Vps35 and RILP are not affected by acute PI(4,5)$ P_{2} $ production. Deletion of PI4K2A greatly reduces PIP5Kγ‐mediated PI(4,5)$ P_{2} $ production in Rab7‐positive endosomes leading to impaired Rab7 inactivation and increased number of LC3‐positive structures with defective autophagosome–lysosome fusion. These results reveal a late endosomal PI4P‐PI(4,5)$ P_{2} $‐dependent regulatory loop that impacts autophagosome flux by affecting Rab7 cycling and PLEKHM1 association. Synopsis Phosphoinositides are key regulators of small GTP‐binding proteins, but how they control the activity of Rab GTPases is poorly understood. PI4K2A and PIP5Kγ act sequentially to generate PI(4,5)$ P_{2} $, which promotes membrane fusion during autophagy through Rab7 inactivation and PLEKHM1 release from late endosomes. PI4K2A is key for PI4P production in Rab7‐positive endosomes.PIP5Kγ converts PI4P to PI(4,5)$ P_{2} $ at late endosomes to inactivate Rab7.PI4K2A or PIP5Kγ depletion impairs acidification of autophagosomes.The conversion of PI4P to PI(4,5)$ P_{2} $ promotes the release of PLEKHM1 from late endosome. Graphical Abstract PI4K2A and PIP5Kγ act sequentially to generate PI(4,5)$ P_{2} $, which promotes membrane fusion during autophagy through Rab7 inactivation and PLEKHM1 release from late endosomes. autophagy (dpeaa)DE-He213 lysosome (dpeaa)DE-He213 phosphatidylinositol 4‐kinase (dpeaa)DE-He213 phosphoinositide (dpeaa)DE-He213 Rab7 (dpeaa)DE-He213 Toth, Daniel J verfasserin aut Sengupta, Nivedita verfasserin aut Kim, Yeun Ju verfasserin aut Balla, Tamas verfasserin (orcid)0000-0002-9077-3335 aut Enthalten in The EMBO Journal Nature Publishing Group UK, 2023 38(2019), 8 vom: 13. März (DE-627)266022529 (DE-600)1467419-1 1460-2075 nnns volume:38 year:2019 number:8 day:13 month:03 https://dx.doi.org/10.15252/embj.2018100312 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_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_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 2019 8 13 03
allfieldsSound	10.15252/embj.2018100312 doi (DE-627)SPR058017569 (SPR)embj.2018100312-e DE-627 ger DE-627 rakwb eng Baba, Takashi verfasserin (orcid)0000-0003-4131-7306 aut Phosphatidylinositol 4,5‐bisphosphate controls Rab7 and PLEKHM1 membrane cycling during autophagosome–lysosome fusion 2019 Text txt rdacontent Computermedien c rdamedia Online-Ressource cr rdacarrier © This article is a U.S. Government work and is in the public domain in the USA 2019 Abstract The small GTPase Rab7 is a key organizer of receptor sorting and lysosomal degradation by recruiting of a variety of effectors depending on its GDP/GTP‐bound state. However, molecular mechanisms that trigger Rab7 inactivation remain elusive. Here we find that, among the endosomal pools, Rab7‐positive compartments possess the highest level of PI4P, which is primarily produced by PI4K2A kinase. Acute conversion of this endosomal PI4P to PI(4,5)$ P_{2} $ causes Rab7 dissociation from late endosomes and releases a regulator of autophagosome–lysosome fusion, PLEKHM1, from the membrane. Rab7 effectors Vps35 and RILP are not affected by acute PI(4,5)$ P_{2} $ production. Deletion of PI4K2A greatly reduces PIP5Kγ‐mediated PI(4,5)$ P_{2} $ production in Rab7‐positive endosomes leading to impaired Rab7 inactivation and increased number of LC3‐positive structures with defective autophagosome–lysosome fusion. These results reveal a late endosomal PI4P‐PI(4,5)$ P_{2} $‐dependent regulatory loop that impacts autophagosome flux by affecting Rab7 cycling and PLEKHM1 association. Synopsis Phosphoinositides are key regulators of small GTP‐binding proteins, but how they control the activity of Rab GTPases is poorly understood. PI4K2A and PIP5Kγ act sequentially to generate PI(4,5)$ P_{2} $, which promotes membrane fusion during autophagy through Rab7 inactivation and PLEKHM1 release from late endosomes. PI4K2A is key for PI4P production in Rab7‐positive endosomes.PIP5Kγ converts PI4P to PI(4,5)$ P_{2} $ at late endosomes to inactivate Rab7.PI4K2A or PIP5Kγ depletion impairs acidification of autophagosomes.The conversion of PI4P to PI(4,5)$ P_{2} $ promotes the release of PLEKHM1 from late endosome. Graphical Abstract PI4K2A and PIP5Kγ act sequentially to generate PI(4,5)$ P_{2} $, which promotes membrane fusion during autophagy through Rab7 inactivation and PLEKHM1 release from late endosomes. autophagy (dpeaa)DE-He213 lysosome (dpeaa)DE-He213 phosphatidylinositol 4‐kinase (dpeaa)DE-He213 phosphoinositide (dpeaa)DE-He213 Rab7 (dpeaa)DE-He213 Toth, Daniel J verfasserin aut Sengupta, Nivedita verfasserin aut Kim, Yeun Ju verfasserin aut Balla, Tamas verfasserin (orcid)0000-0002-9077-3335 aut Enthalten in The EMBO Journal Nature Publishing Group UK, 2023 38(2019), 8 vom: 13. März (DE-627)266022529 (DE-600)1467419-1 1460-2075 nnns volume:38 year:2019 number:8 day:13 month:03 https://dx.doi.org/10.15252/embj.2018100312 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_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_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 2019 8 13 03
language	English
source	Enthalten in The EMBO Journal 38(2019), 8 vom: 13. März volume:38 year:2019 number:8 day:13 month:03
sourceStr	Enthalten in The EMBO Journal 38(2019), 8 vom: 13. März volume:38 year:2019 number:8 day:13 month:03
format_phy_str_mv	Article
institution	findex.gbv.de
topic_facet	autophagy lysosome phosphatidylinositol 4‐kinase phosphoinositide Rab7
isfreeaccess_bool	false
container_title	The EMBO Journal
authorswithroles_txt_mv	Baba, Takashi @@aut@@ Toth, Daniel J @@aut@@ Sengupta, Nivedita @@aut@@ Kim, Yeun Ju @@aut@@ Balla, Tamas @@aut@@
publishDateDaySort_date	2019-03-13T00:00:00Z
hierarchy_top_id	266022529
id	SPR058017569
language_de	englisch
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However, molecular mechanisms that trigger Rab7 inactivation remain elusive. Here we find that, among the endosomal pools, Rab7‐positive compartments possess the highest level of PI4P, which is primarily produced by PI4K2A kinase. Acute conversion of this endosomal PI4P to PI(4,5)$ P_{2} $ causes Rab7 dissociation from late endosomes and releases a regulator of autophagosome–lysosome fusion, PLEKHM1, from the membrane. Rab7 effectors Vps35 and RILP are not affected by acute PI(4,5)$ P_{2} $ production. Deletion of PI4K2A greatly reduces PIP5Kγ‐mediated PI(4,5)$ P_{2} $ production in Rab7‐positive endosomes leading to impaired Rab7 inactivation and increased number of LC3‐positive structures with defective autophagosome–lysosome fusion. These results reveal a late endosomal PI4P‐PI(4,5)$ P_{2} $‐dependent regulatory loop that impacts autophagosome flux by affecting Rab7 cycling and PLEKHM1 association.</subfield></datafield><datafield tag="520" ind1=" " ind2=" "><subfield code="a">Synopsis Phosphoinositides are key regulators of small GTP‐binding proteins, but how they control the activity of Rab GTPases is poorly understood. PI4K2A and PIP5Kγ act sequentially to generate PI(4,5)$ P_{2} $, which promotes membrane fusion during autophagy through Rab7 inactivation and PLEKHM1 release from late endosomes. PI4K2A is key for PI4P production in Rab7‐positive endosomes.PIP5Kγ converts PI4P to PI(4,5)$ P_{2} $ at late endosomes to inactivate Rab7.PI4K2A or PIP5Kγ depletion impairs acidification of autophagosomes.The conversion of PI4P to PI(4,5)$ P_{2} $ promotes the release of PLEKHM1 from late endosome.</subfield></datafield><datafield tag="520" ind1=" " ind2=" "><subfield code="a">Graphical Abstract PI4K2A and PIP5Kγ act sequentially to generate PI(4,5)$ P_{2} $, which promotes membrane fusion during autophagy through Rab7 inactivation and PLEKHM1 release from late endosomes.</subfield></datafield><datafield tag="650" ind1=" " ind2="4"><subfield code="a">autophagy</subfield><subfield code="7">(dpeaa)DE-He213</subfield></datafield><datafield tag="650" ind1=" " ind2="4"><subfield code="a">lysosome</subfield><subfield code="7">(dpeaa)DE-He213</subfield></datafield><datafield tag="650" ind1=" " ind2="4"><subfield code="a">phosphatidylinositol 4‐kinase</subfield><subfield code="7">(dpeaa)DE-He213</subfield></datafield><datafield tag="650" ind1=" " ind2="4"><subfield code="a">phosphoinositide</subfield><subfield code="7">(dpeaa)DE-He213</subfield></datafield><datafield tag="650" ind1=" " ind2="4"><subfield code="a">Rab7</subfield><subfield code="7">(dpeaa)DE-He213</subfield></datafield><datafield tag="700" ind1="1" ind2=" "><subfield code="a">Toth, Daniel J</subfield><subfield code="e">verfasserin</subfield><subfield code="4">aut</subfield></datafield><datafield tag="700" ind1="1" ind2=" "><subfield code="a">Sengupta, Nivedita</subfield><subfield code="e">verfasserin</subfield><subfield code="4">aut</subfield></datafield><datafield tag="700" ind1="1" ind2=" "><subfield code="a">Kim, Yeun Ju</subfield><subfield code="e">verfasserin</subfield><subfield code="4">aut</subfield></datafield><datafield tag="700" ind1="1" ind2=" "><subfield code="a">Balla, Tamas</subfield><subfield code="e">verfasserin</subfield><subfield code="0">(orcid)0000-0002-9077-3335</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(2019), 8 vom: 13. 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author	Baba, Takashi
spellingShingle	Baba, Takashi misc autophagy misc lysosome misc phosphatidylinositol 4‐kinase misc phosphoinositide misc Rab7 Phosphatidylinositol 4,5‐bisphosphate controls Rab7 and PLEKHM1 membrane cycling during autophagosome–lysosome fusion
authorStr	Baba, Takashi
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topic_title	Phosphatidylinositol 4,5‐bisphosphate controls Rab7 and PLEKHM1 membrane cycling during autophagosome–lysosome fusion autophagy (dpeaa)DE-He213 lysosome (dpeaa)DE-He213 phosphatidylinositol 4‐kinase (dpeaa)DE-He213 phosphoinositide (dpeaa)DE-He213 Rab7 (dpeaa)DE-He213
topic	misc autophagy misc lysosome misc phosphatidylinositol 4‐kinase misc phosphoinositide misc Rab7
topic_unstemmed	misc autophagy misc lysosome misc phosphatidylinositol 4‐kinase misc phosphoinositide misc Rab7
topic_browse	misc autophagy misc lysosome misc phosphatidylinositol 4‐kinase misc phosphoinositide misc Rab7
format_facet	Elektronische Aufsätze Aufsätze Elektronische Ressource
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title	Phosphatidylinositol 4,5‐bisphosphate controls Rab7 and PLEKHM1 membrane cycling during autophagosome–lysosome fusion
ctrlnum	(DE-627)SPR058017569 (SPR)embj.2018100312-e
title_full	Phosphatidylinositol 4,5‐bisphosphate controls Rab7 and PLEKHM1 membrane cycling during autophagosome–lysosome fusion
author_sort	Baba, Takashi
journal	The EMBO Journal
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author_browse	Baba, Takashi Toth, Daniel J Sengupta, Nivedita Kim, Yeun Ju Balla, Tamas
container_volume	38
format_se	Elektronische Aufsätze
author-letter	Baba, Takashi
doi_str_mv	10.15252/embj.2018100312
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title_sort	phosphatidylinositol 4,5‐bisphosphate controls rab7 and plekhm1 membrane cycling during autophagosome–lysosome fusion
title_auth	Phosphatidylinositol 4,5‐bisphosphate controls Rab7 and PLEKHM1 membrane cycling during autophagosome–lysosome fusion
abstract	Abstract The small GTPase Rab7 is a key organizer of receptor sorting and lysosomal degradation by recruiting of a variety of effectors depending on its GDP/GTP‐bound state. However, molecular mechanisms that trigger Rab7 inactivation remain elusive. Here we find that, among the endosomal pools, Rab7‐positive compartments possess the highest level of PI4P, which is primarily produced by PI4K2A kinase. Acute conversion of this endosomal PI4P to PI(4,5)$ P_{2} $ causes Rab7 dissociation from late endosomes and releases a regulator of autophagosome–lysosome fusion, PLEKHM1, from the membrane. Rab7 effectors Vps35 and RILP are not affected by acute PI(4,5)$ P_{2} $ production. Deletion of PI4K2A greatly reduces PIP5Kγ‐mediated PI(4,5)$ P_{2} $ production in Rab7‐positive endosomes leading to impaired Rab7 inactivation and increased number of LC3‐positive structures with defective autophagosome–lysosome fusion. These results reveal a late endosomal PI4P‐PI(4,5)$ P_{2} $‐dependent regulatory loop that impacts autophagosome flux by affecting Rab7 cycling and PLEKHM1 association. Synopsis Phosphoinositides are key regulators of small GTP‐binding proteins, but how they control the activity of Rab GTPases is poorly understood. PI4K2A and PIP5Kγ act sequentially to generate PI(4,5)$ P_{2} $, which promotes membrane fusion during autophagy through Rab7 inactivation and PLEKHM1 release from late endosomes. PI4K2A is key for PI4P production in Rab7‐positive endosomes.PIP5Kγ converts PI4P to PI(4,5)$ P_{2} $ at late endosomes to inactivate Rab7.PI4K2A or PIP5Kγ depletion impairs acidification of autophagosomes.The conversion of PI4P to PI(4,5)$ P_{2} $ promotes the release of PLEKHM1 from late endosome. Graphical Abstract PI4K2A and PIP5Kγ act sequentially to generate PI(4,5)$ P_{2} $, which promotes membrane fusion during autophagy through Rab7 inactivation and PLEKHM1 release from late endosomes. © This article is a U.S. Government work and is in the public domain in the USA 2019
abstractGer	Abstract The small GTPase Rab7 is a key organizer of receptor sorting and lysosomal degradation by recruiting of a variety of effectors depending on its GDP/GTP‐bound state. However, molecular mechanisms that trigger Rab7 inactivation remain elusive. Here we find that, among the endosomal pools, Rab7‐positive compartments possess the highest level of PI4P, which is primarily produced by PI4K2A kinase. Acute conversion of this endosomal PI4P to PI(4,5)$ P_{2} $ causes Rab7 dissociation from late endosomes and releases a regulator of autophagosome–lysosome fusion, PLEKHM1, from the membrane. Rab7 effectors Vps35 and RILP are not affected by acute PI(4,5)$ P_{2} $ production. Deletion of PI4K2A greatly reduces PIP5Kγ‐mediated PI(4,5)$ P_{2} $ production in Rab7‐positive endosomes leading to impaired Rab7 inactivation and increased number of LC3‐positive structures with defective autophagosome–lysosome fusion. These results reveal a late endosomal PI4P‐PI(4,5)$ P_{2} $‐dependent regulatory loop that impacts autophagosome flux by affecting Rab7 cycling and PLEKHM1 association. Synopsis Phosphoinositides are key regulators of small GTP‐binding proteins, but how they control the activity of Rab GTPases is poorly understood. PI4K2A and PIP5Kγ act sequentially to generate PI(4,5)$ P_{2} $, which promotes membrane fusion during autophagy through Rab7 inactivation and PLEKHM1 release from late endosomes. PI4K2A is key for PI4P production in Rab7‐positive endosomes.PIP5Kγ converts PI4P to PI(4,5)$ P_{2} $ at late endosomes to inactivate Rab7.PI4K2A or PIP5Kγ depletion impairs acidification of autophagosomes.The conversion of PI4P to PI(4,5)$ P_{2} $ promotes the release of PLEKHM1 from late endosome. Graphical Abstract PI4K2A and PIP5Kγ act sequentially to generate PI(4,5)$ P_{2} $, which promotes membrane fusion during autophagy through Rab7 inactivation and PLEKHM1 release from late endosomes. © This article is a U.S. Government work and is in the public domain in the USA 2019
abstract_unstemmed	Abstract The small GTPase Rab7 is a key organizer of receptor sorting and lysosomal degradation by recruiting of a variety of effectors depending on its GDP/GTP‐bound state. However, molecular mechanisms that trigger Rab7 inactivation remain elusive. Here we find that, among the endosomal pools, Rab7‐positive compartments possess the highest level of PI4P, which is primarily produced by PI4K2A kinase. Acute conversion of this endosomal PI4P to PI(4,5)$ P_{2} $ causes Rab7 dissociation from late endosomes and releases a regulator of autophagosome–lysosome fusion, PLEKHM1, from the membrane. Rab7 effectors Vps35 and RILP are not affected by acute PI(4,5)$ P_{2} $ production. Deletion of PI4K2A greatly reduces PIP5Kγ‐mediated PI(4,5)$ P_{2} $ production in Rab7‐positive endosomes leading to impaired Rab7 inactivation and increased number of LC3‐positive structures with defective autophagosome–lysosome fusion. These results reveal a late endosomal PI4P‐PI(4,5)$ P_{2} $‐dependent regulatory loop that impacts autophagosome flux by affecting Rab7 cycling and PLEKHM1 association. Synopsis Phosphoinositides are key regulators of small GTP‐binding proteins, but how they control the activity of Rab GTPases is poorly understood. PI4K2A and PIP5Kγ act sequentially to generate PI(4,5)$ P_{2} $, which promotes membrane fusion during autophagy through Rab7 inactivation and PLEKHM1 release from late endosomes. PI4K2A is key for PI4P production in Rab7‐positive endosomes.PIP5Kγ converts PI4P to PI(4,5)$ P_{2} $ at late endosomes to inactivate Rab7.PI4K2A or PIP5Kγ depletion impairs acidification of autophagosomes.The conversion of PI4P to PI(4,5)$ P_{2} $ promotes the release of PLEKHM1 from late endosome. Graphical Abstract PI4K2A and PIP5Kγ act sequentially to generate PI(4,5)$ P_{2} $, which promotes membrane fusion during autophagy through Rab7 inactivation and PLEKHM1 release from late endosomes. © This article is a U.S. Government work and is in the public domain in the USA 2019
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container_issue	8
title_short	Phosphatidylinositol 4,5‐bisphosphate controls Rab7 and PLEKHM1 membrane cycling during autophagosome–lysosome fusion
url	https://dx.doi.org/10.15252/embj.2018100312
remote_bool	true
author2	Toth, Daniel J Sengupta, Nivedita Kim, Yeun Ju Balla, Tamas
author2Str	Toth, Daniel J Sengupta, Nivedita Kim, Yeun Ju Balla, Tamas
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doi_str	10.15252/embj.2018100312
up_date	2024-10-24T04:56:03.661Z
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Phosphatidylinositol 4,5‐bisphosphate controls Rab7 and PLEKHM1 membrane cycling during autophagosome–lysosome fusion

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