Eeyarestatin compounds selectively enhance Sec61-mediated Ca2+ leakage from the endoplasmic reticulum

Research output: Contribution to journalArticle

  • External authors:
  • Igor Gamayun
  • Sarah O'Keefe
  • Tillman Pick
  • Marie-Christine Klein
  • Duy Nguyen
  • Craig Mckibbin
  • Michela Piacenti
  • Helen M. Williams
  • Roger Whitehead
  • Volkhard Helms
  • Richard Zimmermann
  • Adolfo Cavalie

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 analogues suggested that the 5-nitrofuran (5-NF) ring of ES1 is crucial for this effect. Accordingly, the analogue 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 analogues studied and induced Ca2+-dependent cell death. Using siRNA 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.

Bibliographical metadata

Original languageEnglish
JournalCell Chemical Biology
Early online date21 Feb 2019
DOIs
Publication statusPublished - 2019