Eeyarestatin I inhibits Sec61-mediated protein translocation at the endoplasmic reticulum

Author:

Cross Benedict C. S.1,McKibbin Craig1,Callan Anna C.1,Roboti Peristera1,Piacenti Michela2,Rabu Catherine1,Wilson Cornelia M.1,Whitehead Roger2,Flitsch Sabine L.23,Pool Martin R.1,High Stephen1,Swanton Eileithyia1

Affiliation:

1. Faculty of Life Sciences, University of Manchester, Oxford Road, Manchester, M13 9PT, UK

2. School of Chemistry, University of Manchester, Oxford Road, Manchester, M13 9PL, UK

3. Manchester Interdisciplinary Biocentre, University of Manchester, 131 Princess Street, Manchester, M1 7DN, UK

Abstract

Production and trafficking of proteins entering the secretory pathway of eukaryotic cells is coordinated at the endoplasmic reticulum (ER) in a process that begins with protein translocation via the membrane-embedded ER translocon. The same complex is also responsible for the co-translational integration of membrane proteins and orchestrates polypeptide modifications that are often essential for protein function. We now show that the previously identified inhibitor of ER-associated degradation (ERAD) eeyarestatin 1 (ESI) is a potent inhibitor of protein translocation. We have characterised this inhibition of ER translocation both in vivo and in vitro, and provide evidence that ESI targets a component of the Sec61 complex that forms the membrane pore of the ER translocon. Further analyses show that ESI acts by preventing the transfer of the nascent polypeptide from the co-translational targeting machinery to the Sec61 complex. These results identify a novel effect of ESI, and suggest that the drug can modulate canonical protein transport from the cytosol into the mammalian ER both in vitro and in vivo.

Publisher

The Company of Biologists

Subject

Cell Biology

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