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

TY - JOUR

T1 - Pre-emptive Quality Control of a Misfolded Membrane Protein by Ribosome-Driven Effects

AU - Lakshminarayan, Ramya

AU - Phillips, Ben P.

AU - Binnian, Imogen L.

AU - Gomez-Navarro, Natalia

AU - Escudero-Urquijo, Norberto

AU - Warren, Alan J.

AU - Miller, Elizabeth A.

N1 - © 2020 MRC Laboratory of Molecular Biology

PY - 2020/3/9

Y1 - 2020/3/9

N2 - 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.

AB - 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.

KW - protein quality control

KW - ribosome-associated quality control

KW - protein folding

KW - endoplasmic reticulum

KW - translational tuning

UR - https://www.scopus.com/pages/publications/85080937190

U2 - 10.1016/j.cub.2019.12.060

DO - 10.1016/j.cub.2019.12.060

M3 - Article

SN - 0960-9822

VL - 30

SP - 854

EP - 864

JO - Current Biology

JF - Current Biology

IS - 5

ER -