Eeyarestatin Compounds Selectively Enhance Sec61-Mediated Ca2+ Leakage from the Endoplasmic Reticulum
Eeyarestatin 1 (ES1) inhibits p97-dependent protein degradation, Sec61-dependent protein translocation into the endoplasmic reticulum (ER), and vesicular transport within the endomembrane system. Here, we show that ES1 impairs Ca 2+ homeostasis by enhancing the Ca 2+ leakage from mammalian ER. A com...
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| Published in | Cell chemical biology Vol. 26; no. 4; pp. 571 - 583.e6 |
|---|---|
| Main Authors | , , , , , , , , , , , , , , |
| Format | Journal Article |
| Language | English |
| Published |
Cell Press
18.04.2019
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| Abstract | Eeyarestatin 1 (ES1) inhibits p97-dependent protein degradation, Sec61-dependent protein translocation into the endoplasmic reticulum (ER), and vesicular transport within the endomembrane system. Here, we show that ES1 impairs Ca
2+
homeostasis by enhancing the Ca
2+
leakage from mammalian ER. A comparison of various ES1 analogs suggested that the 5-nitrofuran (5-NF) ring of ES1 is crucial for this effect. Accordingly, the analog ES24, which conserves the 5-NF domain of ES1, selectively inhibited protein translocation into the ER, displayed the highest potency on ER Ca
2+
leakage of ES1 analogs studied and induced Ca
2+
-dependent cell death. Using small interfering RNA-mediated knockdown of Sec61α, we identified Sec61 complexes as the targets that mediate the gain of Ca
2+
leakage induced by ES1 and ES24. By interacting with the lateral gate of Sec61α, ES1 and ES24 likely capture Sec61 complexes in a Ca
2+
-permeable, open state, in which Sec61 complexes allow Ca
2+
leakage but are translocation incompetent.
•
ES1, ES2, and ES24 deplete Ca
2+
in ER
•
ESR35 and ES47 do not affect cellular Ca
2+
homeostasis
•
The most potent eeyarestatin, ES24, comprises only the 5-nitrofuran domain
•
ES1 and ES24 target Sec61 complexes in ER
Gamayun et al. discovered that eeyarestatins (ESs) interfere with closing mechanisms of Sec61 complexes of the ER and, as a “foot in the door,” stabilize Sec61 complexes in a Ca
2+
-permeable, open state. Specifically, ES24 enhances strongly the Sec61-mediated Ca
2+
leakage from ER and induces Ca
2+
-dependent cell death. |
|---|---|
| AbstractList | Eeyarestatin 1 (ES1) inhibits p97-dependent protein degradation, Sec61-dependent protein translocation into the endoplasmic reticulum (ER), and vesicular transport within the endomembrane system. Here, we show that ES1 impairs Ca
2+
homeostasis by enhancing the Ca
2+
leakage from mammalian ER. A comparison of various ES1 analogs suggested that the 5-nitrofuran (5-NF) ring of ES1 is crucial for this effect. Accordingly, the analog ES24, which conserves the 5-NF domain of ES1, selectively inhibited protein translocation into the ER, displayed the highest potency on ER Ca
2+
leakage of ES1 analogs studied and induced Ca
2+
-dependent cell death. Using small interfering RNA-mediated knockdown of Sec61α, we identified Sec61 complexes as the targets that mediate the gain of Ca
2+
leakage induced by ES1 and ES24. By interacting with the lateral gate of Sec61α, ES1 and ES24 likely capture Sec61 complexes in a Ca
2+
-permeable, open state, in which Sec61 complexes allow Ca
2+
leakage but are translocation incompetent.
•
ES1, ES2, and ES24 deplete Ca
2+
in ER
•
ESR35 and ES47 do not affect cellular Ca
2+
homeostasis
•
The most potent eeyarestatin, ES24, comprises only the 5-nitrofuran domain
•
ES1 and ES24 target Sec61 complexes in ER
Gamayun et al. discovered that eeyarestatins (ESs) interfere with closing mechanisms of Sec61 complexes of the ER and, as a “foot in the door,” stabilize Sec61 complexes in a Ca
2+
-permeable, open state. Specifically, ES24 enhances strongly the Sec61-mediated Ca
2+
leakage from ER and induces Ca
2+
-dependent cell death. |
| Author | Klein, Marie-Christine Pick, Tillman Whitehead, Roger C. Cavalié, Adolfo O'Keefe, Sarah Flitsch, Sabine L. Swanton, Eileithyia Helms, Volkhard McKibbin, Craig Williams, Helen M. Zimmermann, Richard Nguyen, Duy High, Stephen Gamayun, Igor Piacenti, Michela |
| AuthorAffiliation | 2 School of Biological Sciences, Faculty of Biology, Medicine and Health, University of Manchester, Manchester M13 9PT, UK 4 Center for Bioinformatics, Saarland University, 66123 Saarbrücken, Germany 1 Experimental and Clinical Pharmacology and Toxicology, Saarland University, 66421 Homburg, Germany 3 Medical Biochemistry and Molecular Biology, Saarland University, 66421 Homburg, Germany 5 School of Chemistry, University of Manchester, Manchester M13 9PL, UK |
| AuthorAffiliation_xml | – name: 2 School of Biological Sciences, Faculty of Biology, Medicine and Health, University of Manchester, Manchester M13 9PT, UK – name: 1 Experimental and Clinical Pharmacology and Toxicology, Saarland University, 66421 Homburg, Germany – name: 4 Center for Bioinformatics, Saarland University, 66123 Saarbrücken, Germany – name: 5 School of Chemistry, University of Manchester, Manchester M13 9PL, UK – name: 3 Medical Biochemistry and Molecular Biology, Saarland University, 66421 Homburg, Germany |
| Author_xml | – sequence: 1 givenname: Igor surname: Gamayun fullname: Gamayun, Igor – sequence: 2 givenname: Sarah surname: O'Keefe fullname: O'Keefe, Sarah – sequence: 3 givenname: Tillman surname: Pick fullname: Pick, Tillman – sequence: 4 givenname: Marie-Christine surname: Klein fullname: Klein, Marie-Christine – sequence: 5 givenname: Duy surname: Nguyen fullname: Nguyen, Duy – sequence: 6 givenname: Craig surname: McKibbin fullname: McKibbin, Craig – sequence: 7 givenname: Michela surname: Piacenti fullname: Piacenti, Michela – sequence: 8 givenname: Helen M. surname: Williams fullname: Williams, Helen M. – sequence: 9 givenname: Sabine L. surname: Flitsch fullname: Flitsch, Sabine L. – sequence: 10 givenname: Roger C. surname: Whitehead fullname: Whitehead, Roger C. – sequence: 11 givenname: Eileithyia surname: Swanton fullname: Swanton, Eileithyia – sequence: 12 givenname: Volkhard surname: Helms fullname: Helms, Volkhard – sequence: 13 givenname: Stephen surname: High fullname: High, Stephen – sequence: 14 givenname: Richard surname: Zimmermann fullname: Zimmermann, Richard – sequence: 15 givenname: Adolfo surname: Cavalié fullname: Cavalié, Adolfo |
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| Notes | Lead Contact Present address: Eli Lilly Italia S.p.A., 50019 Sesto Fiorentino, Italy Present address: Royal Surrey County Hospital, Egerton Road, Guildford GU2 7XX, UK Present address: Unilever Research and Development, Port Sunlight, Bebington, Wirral CH63 3JW, UK |
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