Eeyarestatin Compounds Selectively Enhance Sec61-Mediated Ca 2+ Leakage from the Endoplasmic Reticulum

Igor Gamayun, Sarah O'Keefe, Tillman Pick, Duy Nguyen, Marie Christine Klein, Craig McKibbin, Michela Piacenti, Helen M. Williams, Sabine L. Flitsch, Roger C. Whitehead, Eileithyia Swanton, Volkhard Helms, Stephen High, Richard Zimmermann, Adolfo Cavalié

Tutkimustuotos: ArtikkelijulkaisuArtikkeliTieteellinenvertaisarvioitu

Abstrakti

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.

Alkuperäiskielienglanti
LehtiCell chemical biology
Vuosikerta26
Numero4
Sivut571-583.e6
ISSN2451-9456
DOI - pysyväislinkit
TilaJulkaistu - 18 huhtik. 2019
Julkaistu ulkoisestiKyllä
OKM-julkaisutyyppiA1 Alkuperäisartikkeli tieteellisessä aikakauslehdessä, vertaisarvioitu

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© 2019 The Authors

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