Endoplasmic Reticulum Transport of Glutathione by Sec61 Is Regulated by Ero1 and Bip

Alise J. Ponsero, Aeid Igbaria, Maxwell A. Darch, Samia Miled, Caryn E. Outten, Jakob R. Winther, Gael Palais, Benoit D'Autréaux, Agnès Delaunay-Moisan, Michel B. Toledano

Research output: Contribution to journalArticlepeer-review

79 Scopus citations

Abstract

In the endoplasmic reticulum (ER), Ero1 catalyzes disulfide bond formation and promotes glutathione (GSH) oxidation to GSSG. Since GSSG cannot be reduced in the ER, maintenance of the ER glutathione redox state and levels likely depends on ER glutathione import and GSSG export. We used quantitative GSH and GSSG biosensors to monitor glutathione import into the ER of yeast cells. We found that glutathione enters the ER by facilitated diffusion through the Sec61 protein-conducting channel, while oxidized Bip (Kar2) inhibits transport. Increased ER glutathione import triggers H2O2-dependent Bip oxidation through Ero1 reductive activation, which inhibits glutathione import in a negative regulatory loop. During ER stress, transport is activated by UPR-dependent Ero1 induction, and cytosolic glutathione levels increase. Thus, the ER redox poise is tuned by reciprocal control of glutathione import and Ero1 activation. The ER protein-conducting channel is permeable to small molecules, provided the driving force of a concentration gradient. Ponsero et al. show that cytosol-to-ER transport of glutathione proceeds via facilitated diffusion through Sec61. Upon import, glutathione activates Ero1 by reduction, causing Bip oxidation and inhibition of glutathione transport. Coupling of glutathione ER import to Ero1 activation provides a basis for glutathione ER redox poise maintenance.

Original languageEnglish
Pages (from-to)962-973.e5
JournalMolecular Cell
Volume67
Issue number6
DOIs
StatePublished - 21 Sep 2017
Externally publishedYes

Keywords

  • Bip
  • Ero1
  • Sec61
  • disulfide bond
  • endoplasmic reticulum
  • glutathione
  • membrane transport
  • oxidative protein folding
  • redox biosensor
  • redox homeostasis

ASJC Scopus subject areas

  • Molecular Biology
  • Cell Biology

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