Eeyarestatin Compounds Selectively Enhance Sec61-Mediated Ca2+ Leakage from the Endoplasmic Reticulum.
Cell Chem Biol
; 26(4): 571-583.e6, 2019 04 18.
Article
em En
| MEDLINE
| ID: mdl-30799222
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 Ca2+ homeostasis by enhancing the Ca2+ 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 Ca2+ leakage of ES1 analogs studied and induced Ca2+-dependent cell death. Using small interfering RNA-mediated knockdown of Sec61α, we identified Sec61 complexes as the targets that mediate the gain of Ca2+ leakage induced by ES1 and ES24. By interacting with the lateral gate of Sec61α, ES1 and ES24 likely capture Sec61 complexes in a Ca2+-permeable, open state, in which Sec61 complexes allow Ca2+ leakage but are translocation incompetent.
Palavras-chave
Protein translocation and degradation; Sec61 complexes of the endoplasmic reticulum; calcium homeostasis; calcium-dependent cytotoxicity; eeyarestatin; endoplasmic reticulum; endoplasmic reticulum calcium content; endoplasmic reticulum calcium homeostasis; endoplasmic reticulum calcium leakage; translocon of endoplasmic reticulum
Texto completo:
1
Base de dados:
MEDLINE
Assunto principal:
Cálcio
/
Retículo Endoplasmático
/
Canais de Translocação SEC
/
Hidrazonas
/
Hidroxiureia
Tipo de estudo:
Prognostic_studies
Limite:
Humans
Idioma:
En
Ano de publicação:
2019
Tipo de documento:
Article