The ER Stress Inducer <span style="font-variant: small-caps"<l</span<-Azetidine-2-Carboxylic Acid Elevates the Levels of Phospho-eIF2α and of LC3-II in a Ca<sup<2+</sup<-Dependent Manner

Accumulation of misfolded proteins in the endoplasmic reticulum (ER) activates the unfolded protein response (UPR) to reduce protein load and restore homeostasis, including via induction of autophagy. We used the proline analogue <span style="font-variant: small-caps;"<l</span<-azetidine-2-carboxylic acid (AZC) to induce ER stress, and assessed its effect on autophagy and Ca<sup<2+</sup< homeostasis. Treatment with 5 mM AZC did not induce poly adenosine diphosphate ribose polymerase (PARP) cleavage while levels of binding immunoglobulin protein (BiP) and phosphorylated eukaryotic translation initiation factor 2α (eIF2α) increased and those of activating transcription factor 6 (ATF6) decreased, indicating activation of the protein kinase RNA-like ER kinase (PERK) and the ATF6 arms of the UPR but not of apoptosis. AZC treatment in combination with bafilomycin A1 (Baf A1) led to elevated levels of the lipidated form of the autophagy marker microtubule-associated protein light chain 3 (LC3), pointing to activation of autophagy. Using the specific PERK inhibitor AMG PERK 44, we could deduce that activation of the PERK branch is required for the AZC-induced lipidation of LC3. Moreover, both the levels of phospho-eIF2α and of lipidated LC3 were strongly reduced when cells were co-treated with the intracellular Ca<sup<2+</sup< chelator 1,2-bis(<i<O</i<-aminophenoxy)ethane-<i<N</i<,<i<N</i<,<i<N′</i<,<i<N′</i<-tetraaceticacid tetra(acetoxy-methyl) ester (BAPTA-AM) but not when co-treated with the Na<sup<+</sup</K<sup<+</sup< ATPase inhibitor ouabain, suggesting an essential role of Ca<sup<2+</sup< in AZC-induced activation of the PERK arm of the UPR and LC3 lipidation. Finally, AZC did not trigger Ca<sup<2+</sup< release from the ER though appeared to decrease the cytosolic Ca<sup<2+</sup< rise induced by thapsigargin while also decreasing the time constant for Ca<sup<2+</sup< clearance. The ER Ca<sup<2+</sup< store content and mitochondrial Ca<sup<2+</sup< uptake however remained unaffected. Ausführliche Beschreibung

Gespeichert in:

Autor*in:	Gemma Roest [verfasserIn] Evelien Hesemans [verfasserIn] Kirsten Welkenhuyzen [verfasserIn] Tomas Luyten [verfasserIn] Nikolai Engedal [verfasserIn] Geert Bultynck [verfasserIn] Jan B. Parys [verfasserIn]

Format:	E-Artikel
Sprache:	Englisch

Erschienen:	2018

Schlagwörter:	autophagy ER stress UPR PERK Ca

Übergeordnetes Werk:	In: Cells - MDPI AG, 2012, 7(2018), 12, p 239
Übergeordnetes Werk:	volume:7 ; year:2018 ; number:12, p 239

Links:	Link aufrufen Link aufrufen Link aufrufen Journal toc

DOI / URN:	10.3390/cells7120239

Katalog-ID:	DOAJ02355391X

Internformat


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allfields	10.3390/cells7120239 doi (DE-627)DOAJ02355391X (DE-599)DOAJf62e5acc6fb24b339abbc9b9f2d2f040 DE-627 ger DE-627 rakwb eng QH301-705.5 Gemma Roest verfasserin aut The ER Stress Inducer <span style="font-variant: small-caps"<l</span<-Azetidine-2-Carboxylic Acid Elevates the Levels of Phospho-eIF2α and of LC3-II in a Ca<sup<2+</sup<-Dependent Manner 2018 Text txt rdacontent Computermedien c rdamedia Online-Ressource cr rdacarrier Accumulation of misfolded proteins in the endoplasmic reticulum (ER) activates the unfolded protein response (UPR) to reduce protein load and restore homeostasis, including via induction of autophagy. We used the proline analogue <span style="font-variant: small-caps;"<l</span<-azetidine-2-carboxylic acid (AZC) to induce ER stress, and assessed its effect on autophagy and Ca<sup<2+</sup< homeostasis. Treatment with 5 mM AZC did not induce poly adenosine diphosphate ribose polymerase (PARP) cleavage while levels of binding immunoglobulin protein (BiP) and phosphorylated eukaryotic translation initiation factor 2α (eIF2α) increased and those of activating transcription factor 6 (ATF6) decreased, indicating activation of the protein kinase RNA-like ER kinase (PERK) and the ATF6 arms of the UPR but not of apoptosis. AZC treatment in combination with bafilomycin A1 (Baf A1) led to elevated levels of the lipidated form of the autophagy marker microtubule-associated protein light chain 3 (LC3), pointing to activation of autophagy. Using the specific PERK inhibitor AMG PERK 44, we could deduce that activation of the PERK branch is required for the AZC-induced lipidation of LC3. Moreover, both the levels of phospho-eIF2α and of lipidated LC3 were strongly reduced when cells were co-treated with the intracellular Ca<sup<2+</sup< chelator 1,2-bis(<i<O</i<-aminophenoxy)ethane-<i<N</i<,<i<N</i<,<i<N′</i<,<i<N′</i<-tetraaceticacid tetra(acetoxy-methyl) ester (BAPTA-AM) but not when co-treated with the Na<sup<+</sup</K<sup<+</sup< ATPase inhibitor ouabain, suggesting an essential role of Ca<sup<2+</sup< in AZC-induced activation of the PERK arm of the UPR and LC3 lipidation. Finally, AZC did not trigger Ca<sup<2+</sup< release from the ER though appeared to decrease the cytosolic Ca<sup<2+</sup< rise induced by thapsigargin while also decreasing the time constant for Ca<sup<2+</sup< clearance. The ER Ca<sup<2+</sup< store content and mitochondrial Ca<sup<2+</sup< uptake however remained unaffected. autophagy ER stress UPR PERK Ca<sup<2+</sup< <span style="font-variant: small-caps"<l</span<-azetidine-2-carboxylic acid Biology (General) Evelien Hesemans verfasserin aut Kirsten Welkenhuyzen verfasserin aut Tomas Luyten verfasserin aut Nikolai Engedal verfasserin aut Geert Bultynck verfasserin aut Jan B. Parys verfasserin aut In Cells MDPI AG, 2012 7(2018), 12, p 239 (DE-627)718622081 (DE-600)2661518-6 20734409 nnns volume:7 year:2018 number:12, p 239 https://doi.org/10.3390/cells7120239 kostenfrei https://doaj.org/article/f62e5acc6fb24b339abbc9b9f2d2f040 kostenfrei https://www.mdpi.com/2073-4409/7/12/239 kostenfrei https://doaj.org/toc/2073-4409 Journal toc kostenfrei GBV_USEFLAG_A SYSFLAG_A GBV_DOAJ GBV_ILN_20 GBV_ILN_22 GBV_ILN_23 GBV_ILN_24 GBV_ILN_39 GBV_ILN_40 GBV_ILN_62 GBV_ILN_63 GBV_ILN_65 GBV_ILN_69 GBV_ILN_70 GBV_ILN_73 GBV_ILN_74 GBV_ILN_95 GBV_ILN_105 GBV_ILN_110 GBV_ILN_151 GBV_ILN_161 GBV_ILN_170 GBV_ILN_206 GBV_ILN_213 GBV_ILN_230 GBV_ILN_285 GBV_ILN_293 GBV_ILN_602 GBV_ILN_2005 GBV_ILN_2009 GBV_ILN_2011 GBV_ILN_2014 GBV_ILN_2055 GBV_ILN_2111 GBV_ILN_4012 GBV_ILN_4037 GBV_ILN_4112 GBV_ILN_4125 GBV_ILN_4126 GBV_ILN_4249 GBV_ILN_4305 GBV_ILN_4306 GBV_ILN_4307 GBV_ILN_4313 GBV_ILN_4322 GBV_ILN_4323 GBV_ILN_4324 GBV_ILN_4325 GBV_ILN_4338 GBV_ILN_4367 GBV_ILN_4700 AR 7 2018 12, p 239
spelling	10.3390/cells7120239 doi (DE-627)DOAJ02355391X (DE-599)DOAJf62e5acc6fb24b339abbc9b9f2d2f040 DE-627 ger DE-627 rakwb eng QH301-705.5 Gemma Roest verfasserin aut The ER Stress Inducer <span style="font-variant: small-caps"<l</span<-Azetidine-2-Carboxylic Acid Elevates the Levels of Phospho-eIF2α and of LC3-II in a Ca<sup<2+</sup<-Dependent Manner 2018 Text txt rdacontent Computermedien c rdamedia Online-Ressource cr rdacarrier Accumulation of misfolded proteins in the endoplasmic reticulum (ER) activates the unfolded protein response (UPR) to reduce protein load and restore homeostasis, including via induction of autophagy. We used the proline analogue <span style="font-variant: small-caps;"<l</span<-azetidine-2-carboxylic acid (AZC) to induce ER stress, and assessed its effect on autophagy and Ca<sup<2+</sup< homeostasis. Treatment with 5 mM AZC did not induce poly adenosine diphosphate ribose polymerase (PARP) cleavage while levels of binding immunoglobulin protein (BiP) and phosphorylated eukaryotic translation initiation factor 2α (eIF2α) increased and those of activating transcription factor 6 (ATF6) decreased, indicating activation of the protein kinase RNA-like ER kinase (PERK) and the ATF6 arms of the UPR but not of apoptosis. AZC treatment in combination with bafilomycin A1 (Baf A1) led to elevated levels of the lipidated form of the autophagy marker microtubule-associated protein light chain 3 (LC3), pointing to activation of autophagy. Using the specific PERK inhibitor AMG PERK 44, we could deduce that activation of the PERK branch is required for the AZC-induced lipidation of LC3. Moreover, both the levels of phospho-eIF2α and of lipidated LC3 were strongly reduced when cells were co-treated with the intracellular Ca<sup<2+</sup< chelator 1,2-bis(<i<O</i<-aminophenoxy)ethane-<i<N</i<,<i<N</i<,<i<N′</i<,<i<N′</i<-tetraaceticacid tetra(acetoxy-methyl) ester (BAPTA-AM) but not when co-treated with the Na<sup<+</sup</K<sup<+</sup< ATPase inhibitor ouabain, suggesting an essential role of Ca<sup<2+</sup< in AZC-induced activation of the PERK arm of the UPR and LC3 lipidation. Finally, AZC did not trigger Ca<sup<2+</sup< release from the ER though appeared to decrease the cytosolic Ca<sup<2+</sup< rise induced by thapsigargin while also decreasing the time constant for Ca<sup<2+</sup< clearance. The ER Ca<sup<2+</sup< store content and mitochondrial Ca<sup<2+</sup< uptake however remained unaffected. autophagy ER stress UPR PERK Ca<sup<2+</sup< <span style="font-variant: small-caps"<l</span<-azetidine-2-carboxylic acid Biology (General) Evelien Hesemans verfasserin aut Kirsten Welkenhuyzen verfasserin aut Tomas Luyten verfasserin aut Nikolai Engedal verfasserin aut Geert Bultynck verfasserin aut Jan B. Parys verfasserin aut In Cells MDPI AG, 2012 7(2018), 12, p 239 (DE-627)718622081 (DE-600)2661518-6 20734409 nnns volume:7 year:2018 number:12, p 239 https://doi.org/10.3390/cells7120239 kostenfrei https://doaj.org/article/f62e5acc6fb24b339abbc9b9f2d2f040 kostenfrei https://www.mdpi.com/2073-4409/7/12/239 kostenfrei https://doaj.org/toc/2073-4409 Journal toc kostenfrei GBV_USEFLAG_A SYSFLAG_A GBV_DOAJ GBV_ILN_20 GBV_ILN_22 GBV_ILN_23 GBV_ILN_24 GBV_ILN_39 GBV_ILN_40 GBV_ILN_62 GBV_ILN_63 GBV_ILN_65 GBV_ILN_69 GBV_ILN_70 GBV_ILN_73 GBV_ILN_74 GBV_ILN_95 GBV_ILN_105 GBV_ILN_110 GBV_ILN_151 GBV_ILN_161 GBV_ILN_170 GBV_ILN_206 GBV_ILN_213 GBV_ILN_230 GBV_ILN_285 GBV_ILN_293 GBV_ILN_602 GBV_ILN_2005 GBV_ILN_2009 GBV_ILN_2011 GBV_ILN_2014 GBV_ILN_2055 GBV_ILN_2111 GBV_ILN_4012 GBV_ILN_4037 GBV_ILN_4112 GBV_ILN_4125 GBV_ILN_4126 GBV_ILN_4249 GBV_ILN_4305 GBV_ILN_4306 GBV_ILN_4307 GBV_ILN_4313 GBV_ILN_4322 GBV_ILN_4323 GBV_ILN_4324 GBV_ILN_4325 GBV_ILN_4338 GBV_ILN_4367 GBV_ILN_4700 AR 7 2018 12, p 239
allfields_unstemmed	10.3390/cells7120239 doi (DE-627)DOAJ02355391X (DE-599)DOAJf62e5acc6fb24b339abbc9b9f2d2f040 DE-627 ger DE-627 rakwb eng QH301-705.5 Gemma Roest verfasserin aut The ER Stress Inducer <span style="font-variant: small-caps"<l</span<-Azetidine-2-Carboxylic Acid Elevates the Levels of Phospho-eIF2α and of LC3-II in a Ca<sup<2+</sup<-Dependent Manner 2018 Text txt rdacontent Computermedien c rdamedia Online-Ressource cr rdacarrier Accumulation of misfolded proteins in the endoplasmic reticulum (ER) activates the unfolded protein response (UPR) to reduce protein load and restore homeostasis, including via induction of autophagy. We used the proline analogue <span style="font-variant: small-caps;"<l</span<-azetidine-2-carboxylic acid (AZC) to induce ER stress, and assessed its effect on autophagy and Ca<sup<2+</sup< homeostasis. Treatment with 5 mM AZC did not induce poly adenosine diphosphate ribose polymerase (PARP) cleavage while levels of binding immunoglobulin protein (BiP) and phosphorylated eukaryotic translation initiation factor 2α (eIF2α) increased and those of activating transcription factor 6 (ATF6) decreased, indicating activation of the protein kinase RNA-like ER kinase (PERK) and the ATF6 arms of the UPR but not of apoptosis. AZC treatment in combination with bafilomycin A1 (Baf A1) led to elevated levels of the lipidated form of the autophagy marker microtubule-associated protein light chain 3 (LC3), pointing to activation of autophagy. Using the specific PERK inhibitor AMG PERK 44, we could deduce that activation of the PERK branch is required for the AZC-induced lipidation of LC3. Moreover, both the levels of phospho-eIF2α and of lipidated LC3 were strongly reduced when cells were co-treated with the intracellular Ca<sup<2+</sup< chelator 1,2-bis(<i<O</i<-aminophenoxy)ethane-<i<N</i<,<i<N</i<,<i<N′</i<,<i<N′</i<-tetraaceticacid tetra(acetoxy-methyl) ester (BAPTA-AM) but not when co-treated with the Na<sup<+</sup</K<sup<+</sup< ATPase inhibitor ouabain, suggesting an essential role of Ca<sup<2+</sup< in AZC-induced activation of the PERK arm of the UPR and LC3 lipidation. Finally, AZC did not trigger Ca<sup<2+</sup< release from the ER though appeared to decrease the cytosolic Ca<sup<2+</sup< rise induced by thapsigargin while also decreasing the time constant for Ca<sup<2+</sup< clearance. The ER Ca<sup<2+</sup< store content and mitochondrial Ca<sup<2+</sup< uptake however remained unaffected. autophagy ER stress UPR PERK Ca<sup<2+</sup< <span style="font-variant: small-caps"<l</span<-azetidine-2-carboxylic acid Biology (General) Evelien Hesemans verfasserin aut Kirsten Welkenhuyzen verfasserin aut Tomas Luyten verfasserin aut Nikolai Engedal verfasserin aut Geert Bultynck verfasserin aut Jan B. Parys verfasserin aut In Cells MDPI AG, 2012 7(2018), 12, p 239 (DE-627)718622081 (DE-600)2661518-6 20734409 nnns volume:7 year:2018 number:12, p 239 https://doi.org/10.3390/cells7120239 kostenfrei https://doaj.org/article/f62e5acc6fb24b339abbc9b9f2d2f040 kostenfrei https://www.mdpi.com/2073-4409/7/12/239 kostenfrei https://doaj.org/toc/2073-4409 Journal toc kostenfrei GBV_USEFLAG_A SYSFLAG_A GBV_DOAJ GBV_ILN_20 GBV_ILN_22 GBV_ILN_23 GBV_ILN_24 GBV_ILN_39 GBV_ILN_40 GBV_ILN_62 GBV_ILN_63 GBV_ILN_65 GBV_ILN_69 GBV_ILN_70 GBV_ILN_73 GBV_ILN_74 GBV_ILN_95 GBV_ILN_105 GBV_ILN_110 GBV_ILN_151 GBV_ILN_161 GBV_ILN_170 GBV_ILN_206 GBV_ILN_213 GBV_ILN_230 GBV_ILN_285 GBV_ILN_293 GBV_ILN_602 GBV_ILN_2005 GBV_ILN_2009 GBV_ILN_2011 GBV_ILN_2014 GBV_ILN_2055 GBV_ILN_2111 GBV_ILN_4012 GBV_ILN_4037 GBV_ILN_4112 GBV_ILN_4125 GBV_ILN_4126 GBV_ILN_4249 GBV_ILN_4305 GBV_ILN_4306 GBV_ILN_4307 GBV_ILN_4313 GBV_ILN_4322 GBV_ILN_4323 GBV_ILN_4324 GBV_ILN_4325 GBV_ILN_4338 GBV_ILN_4367 GBV_ILN_4700 AR 7 2018 12, p 239
allfieldsGer	10.3390/cells7120239 doi (DE-627)DOAJ02355391X (DE-599)DOAJf62e5acc6fb24b339abbc9b9f2d2f040 DE-627 ger DE-627 rakwb eng QH301-705.5 Gemma Roest verfasserin aut The ER Stress Inducer <span style="font-variant: small-caps"<l</span<-Azetidine-2-Carboxylic Acid Elevates the Levels of Phospho-eIF2α and of LC3-II in a Ca<sup<2+</sup<-Dependent Manner 2018 Text txt rdacontent Computermedien c rdamedia Online-Ressource cr rdacarrier Accumulation of misfolded proteins in the endoplasmic reticulum (ER) activates the unfolded protein response (UPR) to reduce protein load and restore homeostasis, including via induction of autophagy. We used the proline analogue <span style="font-variant: small-caps;"<l</span<-azetidine-2-carboxylic acid (AZC) to induce ER stress, and assessed its effect on autophagy and Ca<sup<2+</sup< homeostasis. Treatment with 5 mM AZC did not induce poly adenosine diphosphate ribose polymerase (PARP) cleavage while levels of binding immunoglobulin protein (BiP) and phosphorylated eukaryotic translation initiation factor 2α (eIF2α) increased and those of activating transcription factor 6 (ATF6) decreased, indicating activation of the protein kinase RNA-like ER kinase (PERK) and the ATF6 arms of the UPR but not of apoptosis. AZC treatment in combination with bafilomycin A1 (Baf A1) led to elevated levels of the lipidated form of the autophagy marker microtubule-associated protein light chain 3 (LC3), pointing to activation of autophagy. Using the specific PERK inhibitor AMG PERK 44, we could deduce that activation of the PERK branch is required for the AZC-induced lipidation of LC3. Moreover, both the levels of phospho-eIF2α and of lipidated LC3 were strongly reduced when cells were co-treated with the intracellular Ca<sup<2+</sup< chelator 1,2-bis(<i<O</i<-aminophenoxy)ethane-<i<N</i<,<i<N</i<,<i<N′</i<,<i<N′</i<-tetraaceticacid tetra(acetoxy-methyl) ester (BAPTA-AM) but not when co-treated with the Na<sup<+</sup</K<sup<+</sup< ATPase inhibitor ouabain, suggesting an essential role of Ca<sup<2+</sup< in AZC-induced activation of the PERK arm of the UPR and LC3 lipidation. Finally, AZC did not trigger Ca<sup<2+</sup< release from the ER though appeared to decrease the cytosolic Ca<sup<2+</sup< rise induced by thapsigargin while also decreasing the time constant for Ca<sup<2+</sup< clearance. The ER Ca<sup<2+</sup< store content and mitochondrial Ca<sup<2+</sup< uptake however remained unaffected. autophagy ER stress UPR PERK Ca<sup<2+</sup< <span style="font-variant: small-caps"<l</span<-azetidine-2-carboxylic acid Biology (General) Evelien Hesemans verfasserin aut Kirsten Welkenhuyzen verfasserin aut Tomas Luyten verfasserin aut Nikolai Engedal verfasserin aut Geert Bultynck verfasserin aut Jan B. Parys verfasserin aut In Cells MDPI AG, 2012 7(2018), 12, p 239 (DE-627)718622081 (DE-600)2661518-6 20734409 nnns volume:7 year:2018 number:12, p 239 https://doi.org/10.3390/cells7120239 kostenfrei https://doaj.org/article/f62e5acc6fb24b339abbc9b9f2d2f040 kostenfrei https://www.mdpi.com/2073-4409/7/12/239 kostenfrei https://doaj.org/toc/2073-4409 Journal toc kostenfrei GBV_USEFLAG_A SYSFLAG_A GBV_DOAJ GBV_ILN_20 GBV_ILN_22 GBV_ILN_23 GBV_ILN_24 GBV_ILN_39 GBV_ILN_40 GBV_ILN_62 GBV_ILN_63 GBV_ILN_65 GBV_ILN_69 GBV_ILN_70 GBV_ILN_73 GBV_ILN_74 GBV_ILN_95 GBV_ILN_105 GBV_ILN_110 GBV_ILN_151 GBV_ILN_161 GBV_ILN_170 GBV_ILN_206 GBV_ILN_213 GBV_ILN_230 GBV_ILN_285 GBV_ILN_293 GBV_ILN_602 GBV_ILN_2005 GBV_ILN_2009 GBV_ILN_2011 GBV_ILN_2014 GBV_ILN_2055 GBV_ILN_2111 GBV_ILN_4012 GBV_ILN_4037 GBV_ILN_4112 GBV_ILN_4125 GBV_ILN_4126 GBV_ILN_4249 GBV_ILN_4305 GBV_ILN_4306 GBV_ILN_4307 GBV_ILN_4313 GBV_ILN_4322 GBV_ILN_4323 GBV_ILN_4324 GBV_ILN_4325 GBV_ILN_4338 GBV_ILN_4367 GBV_ILN_4700 AR 7 2018 12, p 239
allfieldsSound	10.3390/cells7120239 doi (DE-627)DOAJ02355391X (DE-599)DOAJf62e5acc6fb24b339abbc9b9f2d2f040 DE-627 ger DE-627 rakwb eng QH301-705.5 Gemma Roest verfasserin aut The ER Stress Inducer <span style="font-variant: small-caps"<l</span<-Azetidine-2-Carboxylic Acid Elevates the Levels of Phospho-eIF2α and of LC3-II in a Ca<sup<2+</sup<-Dependent Manner 2018 Text txt rdacontent Computermedien c rdamedia Online-Ressource cr rdacarrier Accumulation of misfolded proteins in the endoplasmic reticulum (ER) activates the unfolded protein response (UPR) to reduce protein load and restore homeostasis, including via induction of autophagy. We used the proline analogue <span style="font-variant: small-caps;"<l</span<-azetidine-2-carboxylic acid (AZC) to induce ER stress, and assessed its effect on autophagy and Ca<sup<2+</sup< homeostasis. Treatment with 5 mM AZC did not induce poly adenosine diphosphate ribose polymerase (PARP) cleavage while levels of binding immunoglobulin protein (BiP) and phosphorylated eukaryotic translation initiation factor 2α (eIF2α) increased and those of activating transcription factor 6 (ATF6) decreased, indicating activation of the protein kinase RNA-like ER kinase (PERK) and the ATF6 arms of the UPR but not of apoptosis. AZC treatment in combination with bafilomycin A1 (Baf A1) led to elevated levels of the lipidated form of the autophagy marker microtubule-associated protein light chain 3 (LC3), pointing to activation of autophagy. Using the specific PERK inhibitor AMG PERK 44, we could deduce that activation of the PERK branch is required for the AZC-induced lipidation of LC3. Moreover, both the levels of phospho-eIF2α and of lipidated LC3 were strongly reduced when cells were co-treated with the intracellular Ca<sup<2+</sup< chelator 1,2-bis(<i<O</i<-aminophenoxy)ethane-<i<N</i<,<i<N</i<,<i<N′</i<,<i<N′</i<-tetraaceticacid tetra(acetoxy-methyl) ester (BAPTA-AM) but not when co-treated with the Na<sup<+</sup</K<sup<+</sup< ATPase inhibitor ouabain, suggesting an essential role of Ca<sup<2+</sup< in AZC-induced activation of the PERK arm of the UPR and LC3 lipidation. Finally, AZC did not trigger Ca<sup<2+</sup< release from the ER though appeared to decrease the cytosolic Ca<sup<2+</sup< rise induced by thapsigargin while also decreasing the time constant for Ca<sup<2+</sup< clearance. The ER Ca<sup<2+</sup< store content and mitochondrial Ca<sup<2+</sup< uptake however remained unaffected. autophagy ER stress UPR PERK Ca<sup<2+</sup< <span style="font-variant: small-caps"<l</span<-azetidine-2-carboxylic acid Biology (General) Evelien Hesemans verfasserin aut Kirsten Welkenhuyzen verfasserin aut Tomas Luyten verfasserin aut Nikolai Engedal verfasserin aut Geert Bultynck verfasserin aut Jan B. Parys verfasserin aut In Cells MDPI AG, 2012 7(2018), 12, p 239 (DE-627)718622081 (DE-600)2661518-6 20734409 nnns volume:7 year:2018 number:12, p 239 https://doi.org/10.3390/cells7120239 kostenfrei https://doaj.org/article/f62e5acc6fb24b339abbc9b9f2d2f040 kostenfrei https://www.mdpi.com/2073-4409/7/12/239 kostenfrei https://doaj.org/toc/2073-4409 Journal toc kostenfrei GBV_USEFLAG_A SYSFLAG_A GBV_DOAJ GBV_ILN_20 GBV_ILN_22 GBV_ILN_23 GBV_ILN_24 GBV_ILN_39 GBV_ILN_40 GBV_ILN_62 GBV_ILN_63 GBV_ILN_65 GBV_ILN_69 GBV_ILN_70 GBV_ILN_73 GBV_ILN_74 GBV_ILN_95 GBV_ILN_105 GBV_ILN_110 GBV_ILN_151 GBV_ILN_161 GBV_ILN_170 GBV_ILN_206 GBV_ILN_213 GBV_ILN_230 GBV_ILN_285 GBV_ILN_293 GBV_ILN_602 GBV_ILN_2005 GBV_ILN_2009 GBV_ILN_2011 GBV_ILN_2014 GBV_ILN_2055 GBV_ILN_2111 GBV_ILN_4012 GBV_ILN_4037 GBV_ILN_4112 GBV_ILN_4125 GBV_ILN_4126 GBV_ILN_4249 GBV_ILN_4305 GBV_ILN_4306 GBV_ILN_4307 GBV_ILN_4313 GBV_ILN_4322 GBV_ILN_4323 GBV_ILN_4324 GBV_ILN_4325 GBV_ILN_4338 GBV_ILN_4367 GBV_ILN_4700 AR 7 2018 12, p 239
language	English
source	In Cells 7(2018), 12, p 239 volume:7 year:2018 number:12, p 239
sourceStr	In Cells 7(2018), 12, p 239 volume:7 year:2018 number:12, p 239
format_phy_str_mv	Article
institution	findex.gbv.de
topic_facet	autophagy ER stress UPR PERK Ca<sup<2+</sup< <span style="font-variant: small-caps"<l</span<-azetidine-2-carboxylic acid Biology (General)
isfreeaccess_bool	true
container_title	Cells
authorswithroles_txt_mv	Gemma Roest @@aut@@ Evelien Hesemans @@aut@@ Kirsten Welkenhuyzen @@aut@@ Tomas Luyten @@aut@@ Nikolai Engedal @@aut@@ Geert Bultynck @@aut@@ Jan B. Parys @@aut@@
publishDateDaySort_date	2018-01-01T00:00:00Z
hierarchy_top_id	718622081
id	DOAJ02355391X
language_de	englisch
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callnumber-first	Q - Science
author	Gemma Roest
spellingShingle	Gemma Roest misc QH301-705.5 misc autophagy misc ER stress misc UPR misc PERK misc Ca<sup<2+</sup< misc <span style="font-variant: small-caps"<l</span<-azetidine-2-carboxylic acid misc Biology (General) The ER Stress Inducer <span style="font-variant: small-caps"<l</span<-Azetidine-2-Carboxylic Acid Elevates the Levels of Phospho-eIF2α and of LC3-II in a Ca<sup<2+</sup<-Dependent Manner
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topic_title	QH301-705.5 The ER Stress Inducer <span style="font-variant: small-caps"<l</span<-Azetidine-2-Carboxylic Acid Elevates the Levels of Phospho-eIF2α and of LC3-II in a Ca<sup<2+</sup<-Dependent Manner autophagy ER stress UPR PERK Ca<sup<2+</sup< <span style="font-variant: small-caps"<l</span<-azetidine-2-carboxylic acid
topic	misc QH301-705.5 misc autophagy misc ER stress misc UPR misc PERK misc Ca<sup<2+</sup< misc <span style="font-variant: small-caps"<l</span<-azetidine-2-carboxylic acid misc Biology (General)
topic_unstemmed	misc QH301-705.5 misc autophagy misc ER stress misc UPR misc PERK misc Ca<sup<2+</sup< misc <span style="font-variant: small-caps"<l</span<-azetidine-2-carboxylic acid misc Biology (General)
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title	The ER Stress Inducer <span style="font-variant: small-caps"<l</span<-Azetidine-2-Carboxylic Acid Elevates the Levels of Phospho-eIF2α and of LC3-II in a Ca<sup<2+</sup<-Dependent Manner
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title_full	The ER Stress Inducer <span style="font-variant: small-caps"<l</span<-Azetidine-2-Carboxylic Acid Elevates the Levels of Phospho-eIF2α and of LC3-II in a Ca<sup<2+</sup<-Dependent Manner
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author_browse	Gemma Roest Evelien Hesemans Kirsten Welkenhuyzen Tomas Luyten Nikolai Engedal Geert Bultynck Jan B. Parys
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author-letter	Gemma Roest
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title_sort	er stress inducer <span style="font-variant: small-caps"<l</span<-azetidine-2-carboxylic acid elevates the levels of phospho-eif2α and of lc3-ii in a ca<sup<2+</sup<-dependent manner
callnumber	QH301-705.5
title_auth	The ER Stress Inducer <span style="font-variant: small-caps"<l</span<-Azetidine-2-Carboxylic Acid Elevates the Levels of Phospho-eIF2α and of LC3-II in a Ca<sup<2+</sup<-Dependent Manner
abstract	Accumulation of misfolded proteins in the endoplasmic reticulum (ER) activates the unfolded protein response (UPR) to reduce protein load and restore homeostasis, including via induction of autophagy. We used the proline analogue <span style="font-variant: small-caps;"<l</span<-azetidine-2-carboxylic acid (AZC) to induce ER stress, and assessed its effect on autophagy and Ca<sup<2+</sup< homeostasis. Treatment with 5 mM AZC did not induce poly adenosine diphosphate ribose polymerase (PARP) cleavage while levels of binding immunoglobulin protein (BiP) and phosphorylated eukaryotic translation initiation factor 2α (eIF2α) increased and those of activating transcription factor 6 (ATF6) decreased, indicating activation of the protein kinase RNA-like ER kinase (PERK) and the ATF6 arms of the UPR but not of apoptosis. AZC treatment in combination with bafilomycin A1 (Baf A1) led to elevated levels of the lipidated form of the autophagy marker microtubule-associated protein light chain 3 (LC3), pointing to activation of autophagy. Using the specific PERK inhibitor AMG PERK 44, we could deduce that activation of the PERK branch is required for the AZC-induced lipidation of LC3. Moreover, both the levels of phospho-eIF2α and of lipidated LC3 were strongly reduced when cells were co-treated with the intracellular Ca<sup<2+</sup< chelator 1,2-bis(<i<O</i<-aminophenoxy)ethane-<i<N</i<,<i<N</i<,<i<N′</i<,<i<N′</i<-tetraaceticacid tetra(acetoxy-methyl) ester (BAPTA-AM) but not when co-treated with the Na<sup<+</sup</K<sup<+</sup< ATPase inhibitor ouabain, suggesting an essential role of Ca<sup<2+</sup< in AZC-induced activation of the PERK arm of the UPR and LC3 lipidation. Finally, AZC did not trigger Ca<sup<2+</sup< release from the ER though appeared to decrease the cytosolic Ca<sup<2+</sup< rise induced by thapsigargin while also decreasing the time constant for Ca<sup<2+</sup< clearance. The ER Ca<sup<2+</sup< store content and mitochondrial Ca<sup<2+</sup< uptake however remained unaffected.
abstractGer	Accumulation of misfolded proteins in the endoplasmic reticulum (ER) activates the unfolded protein response (UPR) to reduce protein load and restore homeostasis, including via induction of autophagy. We used the proline analogue <span style="font-variant: small-caps;"<l</span<-azetidine-2-carboxylic acid (AZC) to induce ER stress, and assessed its effect on autophagy and Ca<sup<2+</sup< homeostasis. Treatment with 5 mM AZC did not induce poly adenosine diphosphate ribose polymerase (PARP) cleavage while levels of binding immunoglobulin protein (BiP) and phosphorylated eukaryotic translation initiation factor 2α (eIF2α) increased and those of activating transcription factor 6 (ATF6) decreased, indicating activation of the protein kinase RNA-like ER kinase (PERK) and the ATF6 arms of the UPR but not of apoptosis. AZC treatment in combination with bafilomycin A1 (Baf A1) led to elevated levels of the lipidated form of the autophagy marker microtubule-associated protein light chain 3 (LC3), pointing to activation of autophagy. Using the specific PERK inhibitor AMG PERK 44, we could deduce that activation of the PERK branch is required for the AZC-induced lipidation of LC3. Moreover, both the levels of phospho-eIF2α and of lipidated LC3 were strongly reduced when cells were co-treated with the intracellular Ca<sup<2+</sup< chelator 1,2-bis(<i<O</i<-aminophenoxy)ethane-<i<N</i<,<i<N</i<,<i<N′</i<,<i<N′</i<-tetraaceticacid tetra(acetoxy-methyl) ester (BAPTA-AM) but not when co-treated with the Na<sup<+</sup</K<sup<+</sup< ATPase inhibitor ouabain, suggesting an essential role of Ca<sup<2+</sup< in AZC-induced activation of the PERK arm of the UPR and LC3 lipidation. Finally, AZC did not trigger Ca<sup<2+</sup< release from the ER though appeared to decrease the cytosolic Ca<sup<2+</sup< rise induced by thapsigargin while also decreasing the time constant for Ca<sup<2+</sup< clearance. The ER Ca<sup<2+</sup< store content and mitochondrial Ca<sup<2+</sup< uptake however remained unaffected.
abstract_unstemmed	Accumulation of misfolded proteins in the endoplasmic reticulum (ER) activates the unfolded protein response (UPR) to reduce protein load and restore homeostasis, including via induction of autophagy. We used the proline analogue <span style="font-variant: small-caps;"<l</span<-azetidine-2-carboxylic acid (AZC) to induce ER stress, and assessed its effect on autophagy and Ca<sup<2+</sup< homeostasis. Treatment with 5 mM AZC did not induce poly adenosine diphosphate ribose polymerase (PARP) cleavage while levels of binding immunoglobulin protein (BiP) and phosphorylated eukaryotic translation initiation factor 2α (eIF2α) increased and those of activating transcription factor 6 (ATF6) decreased, indicating activation of the protein kinase RNA-like ER kinase (PERK) and the ATF6 arms of the UPR but not of apoptosis. AZC treatment in combination with bafilomycin A1 (Baf A1) led to elevated levels of the lipidated form of the autophagy marker microtubule-associated protein light chain 3 (LC3), pointing to activation of autophagy. Using the specific PERK inhibitor AMG PERK 44, we could deduce that activation of the PERK branch is required for the AZC-induced lipidation of LC3. Moreover, both the levels of phospho-eIF2α and of lipidated LC3 were strongly reduced when cells were co-treated with the intracellular Ca<sup<2+</sup< chelator 1,2-bis(<i<O</i<-aminophenoxy)ethane-<i<N</i<,<i<N</i<,<i<N′</i<,<i<N′</i<-tetraaceticacid tetra(acetoxy-methyl) ester (BAPTA-AM) but not when co-treated with the Na<sup<+</sup</K<sup<+</sup< ATPase inhibitor ouabain, suggesting an essential role of Ca<sup<2+</sup< in AZC-induced activation of the PERK arm of the UPR and LC3 lipidation. Finally, AZC did not trigger Ca<sup<2+</sup< release from the ER though appeared to decrease the cytosolic Ca<sup<2+</sup< rise induced by thapsigargin while also decreasing the time constant for Ca<sup<2+</sup< clearance. The ER Ca<sup<2+</sup< store content and mitochondrial Ca<sup<2+</sup< uptake however remained unaffected.
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title_short	The ER Stress Inducer <span style="font-variant: small-caps"<l</span<-Azetidine-2-Carboxylic Acid Elevates the Levels of Phospho-eIF2α and of LC3-II in a Ca<sup<2+</sup<-Dependent Manner
url	https://doi.org/10.3390/cells7120239 https://doaj.org/article/f62e5acc6fb24b339abbc9b9f2d2f040 https://www.mdpi.com/2073-4409/7/12/239 https://doaj.org/toc/2073-4409
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We used the proline analogue <span style="font-variant: small-caps;"<l</span<-azetidine-2-carboxylic acid (AZC) to induce ER stress, and assessed its effect on autophagy and Ca<sup<2+</sup< homeostasis. Treatment with 5 mM AZC did not induce poly adenosine diphosphate ribose polymerase (PARP) cleavage while levels of binding immunoglobulin protein (BiP) and phosphorylated eukaryotic translation initiation factor 2α (eIF2α) increased and those of activating transcription factor 6 (ATF6) decreased, indicating activation of the protein kinase RNA-like ER kinase (PERK) and the ATF6 arms of the UPR but not of apoptosis. AZC treatment in combination with bafilomycin A1 (Baf A1) led to elevated levels of the lipidated form of the autophagy marker microtubule-associated protein light chain 3 (LC3), pointing to activation of autophagy. Using the specific PERK inhibitor AMG PERK 44, we could deduce that activation of the PERK branch is required for the AZC-induced lipidation of LC3. Moreover, both the levels of phospho-eIF2α and of lipidated LC3 were strongly reduced when cells were co-treated with the intracellular Ca<sup<2+</sup< chelator 1,2-bis(<i<O</i<-aminophenoxy)ethane-<i<N</i<,<i<N</i<,<i<N′</i<,<i<N′</i<-tetraaceticacid tetra(acetoxy-methyl) ester (BAPTA-AM) but not when co-treated with the Na<sup<+</sup</K<sup<+</sup< ATPase inhibitor ouabain, suggesting an essential role of Ca<sup<2+</sup< in AZC-induced activation of the PERK arm of the UPR and LC3 lipidation. Finally, AZC did not trigger Ca<sup<2+</sup< release from the ER though appeared to decrease the cytosolic Ca<sup<2+</sup< rise induced by thapsigargin while also decreasing the time constant for Ca<sup<2+</sup< clearance. 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The ER Stress Inducer <span style="font-variant: small-caps"<l</span<-Azetidine-2-Carboxylic Acid Elevates the Levels of Phospho-eIF2α and of LC3-II in a Ca<sup<2+</sup<-Dependent Manner

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