Eeyarestatin Compounds Selectively Enhance Sec61-Mediated Ca2+ Leakage from the Endoplasmic Reticulum

Cell Chemical Biology
Igor GamayunAdolfo Cavalié

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.

Citations

Jul 22, 2019·FEBS Letters·Sarah HaßdenteufelRichard Zimmermann
Feb 19, 2020·Natural Product Reports·Hendrik Luesch, Ville O Paavilainen
May 4, 2021·Frontiers in Molecular Biosciences·Julia OswaldHans-Georg Koch
May 8, 2021·The FEBS Journal·Sarah O'KeefeStephen High
Sep 25, 2019·Journal of Medicinal Chemistry·Donna M HurynPeter Wipf
Dec 3, 2020·The Journal of Organic Chemistry·Guanghui ZongWei Q Shi
Jul 2, 2020·ACS Chemical Biology·Dale TranterVille O Paavilainen

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