• An alternative pathway for membrane protein biogenesis at the endoplasmic reticulum

      O’Keefe, Sarah; orcid: 0000-0002-1744-0198; email: sarah.okeefe@manchester.ac.uk; Zong, Guanghui; orcid: 0000-0002-7335-039X; Duah, Kwabena B.; Andrews, Lauren E.; Shi, Wei Q.; orcid: 0000-0001-5453-1753; High, Stephen; orcid: 0000-0002-4532-8152; email: stephen.high@manchester.ac.uk (Nature Publishing Group UK, 2021-07-01)
      Abstract: The heterotrimeric Sec61 complex is a major site for the biogenesis of transmembrane proteins (TMPs), accepting nascent TMP precursors that are targeted to the endoplasmic reticulum (ER) by the signal recognition particle (SRP). Unlike most single-spanning membrane proteins, the integration of type III TMPs is completely resistant to small molecule inhibitors of the Sec61 translocon. Using siRNA-mediated depletion of specific ER components, in combination with the potent Sec61 inhibitor ipomoeassin F (Ipom-F), we show that type III TMPs utilise a distinct pathway for membrane integration at the ER. Hence, following SRP-mediated delivery to the ER, type III TMPs can uniquely access the membrane insertase activity of the ER membrane complex (EMC) via a mechanism that is facilitated by the Sec61 translocon. This alternative EMC-mediated insertion pathway allows type III TMPs to bypass the Ipom-F-mediated blockade of membrane integration that is seen with obligate Sec61 clients.