Ipomoeassin-F disrupts multiple aspects of secretory protein biogenesis

Abstract The Sec61 complex translocates nascent polypeptides into and across the membrane of the endoplasmic reticulum (ER), providing access to the secretory pathway. In this study, we show that Ipomoeassin-F (Ipom-F), a selective inhibitor of protein entry into the ER lumen, blocks the in vitro tr...

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Autores principales:	Peristera Roboti, Sarah O’Keefe, Kwabena B. Duah, Wei Q. Shi, Stephen High
Formato:	article
Lenguaje:	EN
Publicado:	Nature Portfolio 2021
Materias:	Medicine R Science Q
Acceso en línea:	https://doaj.org/article/84a590a1a842429faa233bc88b29e96b
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spelling	oai:doaj.org-article:84a590a1a842429faa233bc88b29e96b2021-12-02T15:02:23ZIpomoeassin-F disrupts multiple aspects of secretory protein biogenesis10.1038/s41598-021-91107-42045-2322https://doaj.org/article/84a590a1a842429faa233bc88b29e96b2021-06-01T00:00:00Zhttps://doi.org/10.1038/s41598-021-91107-4https://doaj.org/toc/2045-2322Abstract The Sec61 complex translocates nascent polypeptides into and across the membrane of the endoplasmic reticulum (ER), providing access to the secretory pathway. In this study, we show that Ipomoeassin-F (Ipom-F), a selective inhibitor of protein entry into the ER lumen, blocks the in vitro translocation of certain secretory proteins and ER lumenal folding factors whilst barely affecting others such as albumin. The effects of Ipom-F on protein secretion from HepG2 cells are twofold: reduced ER translocation combined, in some cases, with defective ER lumenal folding. This latter issue is most likely a consequence of Ipom-F preventing the cell from replenishing its ER lumenal chaperones. Ipom-F treatment results in two cellular stress responses: firstly, an upregulation of stress-inducible cytosolic chaperones, Hsp70 and Hsp90; secondly, an atypical unfolded protein response (UPR) linked to the Ipom-F-mediated perturbation of ER function. Hence, although levels of spliced XBP1 and CHOP mRNA and ATF4 protein increase with Ipom-F, the accompanying increase in the levels of ER lumenal BiP and GRP94 seen with tunicamycin are not observed. In short, although Ipom-F reduces the biosynthetic load of newly synthesised secretory proteins entering the ER lumen, its effects on the UPR preclude the cell restoring ER homeostasis.Peristera RobotiSarah O’KeefeKwabena B. DuahWei Q. ShiStephen HighNature PortfolioarticleMedicineRScienceQENScientific Reports, Vol 11, Iss 1, Pp 1-16 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Science Q
spellingShingle	Medicine R Science Q Peristera Roboti Sarah O’Keefe Kwabena B. Duah Wei Q. Shi Stephen High Ipomoeassin-F disrupts multiple aspects of secretory protein biogenesis
description	Abstract The Sec61 complex translocates nascent polypeptides into and across the membrane of the endoplasmic reticulum (ER), providing access to the secretory pathway. In this study, we show that Ipomoeassin-F (Ipom-F), a selective inhibitor of protein entry into the ER lumen, blocks the in vitro translocation of certain secretory proteins and ER lumenal folding factors whilst barely affecting others such as albumin. The effects of Ipom-F on protein secretion from HepG2 cells are twofold: reduced ER translocation combined, in some cases, with defective ER lumenal folding. This latter issue is most likely a consequence of Ipom-F preventing the cell from replenishing its ER lumenal chaperones. Ipom-F treatment results in two cellular stress responses: firstly, an upregulation of stress-inducible cytosolic chaperones, Hsp70 and Hsp90; secondly, an atypical unfolded protein response (UPR) linked to the Ipom-F-mediated perturbation of ER function. Hence, although levels of spliced XBP1 and CHOP mRNA and ATF4 protein increase with Ipom-F, the accompanying increase in the levels of ER lumenal BiP and GRP94 seen with tunicamycin are not observed. In short, although Ipom-F reduces the biosynthetic load of newly synthesised secretory proteins entering the ER lumen, its effects on the UPR preclude the cell restoring ER homeostasis.
format	article
author	Peristera Roboti Sarah O’Keefe Kwabena B. Duah Wei Q. Shi Stephen High
author_facet	Peristera Roboti Sarah O’Keefe Kwabena B. Duah Wei Q. Shi Stephen High
author_sort	Peristera Roboti
title	Ipomoeassin-F disrupts multiple aspects of secretory protein biogenesis
title_short	Ipomoeassin-F disrupts multiple aspects of secretory protein biogenesis
title_full	Ipomoeassin-F disrupts multiple aspects of secretory protein biogenesis
title_fullStr	Ipomoeassin-F disrupts multiple aspects of secretory protein biogenesis
title_full_unstemmed	Ipomoeassin-F disrupts multiple aspects of secretory protein biogenesis
title_sort	ipomoeassin-f disrupts multiple aspects of secretory protein biogenesis
publisher	Nature Portfolio
publishDate	2021
url	https://doaj.org/article/84a590a1a842429faa233bc88b29e96b
work_keys_str_mv	AT peristeraroboti ipomoeassinfdisruptsmultipleaspectsofsecretoryproteinbiogenesis AT sarahokeefe ipomoeassinfdisruptsmultipleaspectsofsecretoryproteinbiogenesis AT kwabenabduah ipomoeassinfdisruptsmultipleaspectsofsecretoryproteinbiogenesis AT weiqshi ipomoeassinfdisruptsmultipleaspectsofsecretoryproteinbiogenesis AT stephenhigh ipomoeassinfdisruptsmultipleaspectsofsecretoryproteinbiogenesis
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Ipomoeassin-F disrupts multiple aspects of secretory protein biogenesis

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