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<...
Ausführliche Beschreibung
Autor*in: |
Gemma Roest [verfasserIn] Evelien Hesemans [verfasserIn] Kirsten Welkenhuyzen [verfasserIn] Tomas Luyten [verfasserIn] Nikolai Engedal [verfasserIn] Geert Bultynck [verfasserIn] Jan B. Parys [verfasserIn] |
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Format: |
E-Artikel |
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Sprache: |
Englisch |
Erschienen: |
2018 |
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Schlagwörter: |
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Übergeordnetes Werk: |
In: Cells - MDPI AG, 2012, 7(2018), 12, p 239 |
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Übergeordnetes Werk: |
volume:7 ; year:2018 ; number:12, p 239 |
Links: |
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DOI / URN: |
10.3390/cells7120239 |
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Katalog-ID: |
DOAJ02355391X |
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245 | 1 | 4 | |a 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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520 | |a 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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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 |
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Gemma Roest @@aut@@ Evelien Hesemans @@aut@@ Kirsten Welkenhuyzen @@aut@@ Tomas Luyten @@aut@@ Nikolai Engedal @@aut@@ Geert Bultynck @@aut@@ Jan B. Parys @@aut@@ |
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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 |
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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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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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Gemma Roest Evelien Hesemans Kirsten Welkenhuyzen Tomas Luyten Nikolai Engedal Geert Bultynck Jan B. Parys |
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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 |
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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 |
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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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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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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