An alternative pathway for membrane protein biogenesis at the endoplasmic reticulum

Commun Biol. 2021 Jul 1;4(1):828. doi: 10.1038/s42003-021-02363-z.

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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Endoplasmic Reticulum / drug effects
  • Endoplasmic Reticulum / metabolism*
  • Glycoconjugates / pharmacology
  • HeLa Cells
  • Humans
  • Immunoblotting
  • Intracellular Membranes / drug effects
  • Intracellular Membranes / metabolism*
  • Membrane Proteins / metabolism*
  • Models, Biological
  • Protein Biosynthesis*
  • Protein Transport / drug effects
  • RNA Interference
  • SEC Translocation Channels / genetics
  • SEC Translocation Channels / metabolism*
  • Signal Recognition Particle / metabolism

Substances

  • Glycoconjugates
  • Membrane Proteins
  • SEC Translocation Channels
  • Signal Recognition Particle
  • ipomoeassin F