Pre-emptive Quality Control of a Misfolded Membrane Protein by Ribosome-Driven Effects

Ramya Lakshminarayan, Ben P. Phillips, Imogen L. Binnian, Natalia Gomez-Navarro, Norberto Escudero-Urquijo, Alan J. Warren, Elizabeth A. Miller (Lead / Corresponding author)

Research output: Contribution to journalArticlepeer-review

31 Citations (Scopus)

Abstract

Cells possess multiple mechanisms that protect against the accumulation of toxic aggregation-prone proteins. Here, we identify a pre-emptive pathway that reduces synthesis of membrane proteins that have failed to properly assemble in the endoplasmic reticulum (ER). We show that loss of the ER membrane complex (EMC) or mutation of the Sec61 translocon causes reduced synthesis of misfolded forms of the yeast ABC transporter Yor1. Synthesis defects are rescued by various ribosomal mutations, as well as by reducing cellular ribosome abundance. Genetic and biochemical evidence point to a ribosome-associated quality-control pathway triggered by ribosome collisions when membrane domain insertion and/or folding fails. In support of this model, translation initiation also contributes to synthesis defects, likely by modulating ribosome abundance on the message. Examination of translation efficiency across the yeast membrane proteome revealed that polytopic membrane proteins have relatively low ribosome abundance, providing evidence for translational tuning to balance protein synthesis and folding. We propose that by modulating translation rates of poorly folded proteins, cells can pre-emptively protect themselves from potentially toxic aberrant transmembrane proteins.
Original languageEnglish
Pages (from-to)854-864
Number of pages17
JournalCurrent Biology
Volume30
Issue number5
Early online date16 Jan 2020
DOIs
Publication statusPublished - 9 Mar 2020

Keywords

  • protein quality control
  • ribosome-associated quality control
  • protein folding
  • endoplasmic reticulum
  • translational tuning

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