Ipomoeassin-F disrupts multiple aspects of secretory protein biogenesis
AuthorsRoboti, Peristera; email: firstname.lastname@example.org
Duah, Kwabena B.
Shi, Wei Q.
High, Stephen; email: email@example.com
MetadataShow full item record
AbstractAbstract: 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.
CitationScientific Reports, volume 11, issue 1, page 11562
PublisherNature Publishing Group UK
DescriptionFrom Springer Nature via Jisc Publications Router
History: received 2021-02-25, accepted 2021-05-11, registration 2021-05-24, pub-electronic 2021-06-02, online 2021-06-02, collection 2021-12
Publication status: Published
Funder: National Institute of General Medical Sciences; doi: http://dx.doi.org/10.13039/100000057; Grant(s): AREA grant 2R15GM116032-02A1
Funder: Ball State University; doi: http://dx.doi.org/10.13039/100008326; Grant(s): Provost Startup Award
Funder: Wellcome Trust; doi: http://dx.doi.org/10.13039/100010269; Grant(s): 204957/Z/16/Z