Dataset Information

Transmembrane thioredoxin-related protein TMX1 is reversibly oxidized in response to protein accumulation in the endoplasmic reticulum.

ABSTRACT: Numerous secretory and membrane proteins undergo post-translational modifications in the endoplasmic reticulum (ER), and the formation of disulfide bonds is a modification that is critical for proper protein folding. The mammalian ER contains a large family of oxidoreductases that are considered to catalyze thiol/disulfide exchange and ensure the maintenance of a redox environment within the ER. Disruption of ER homeostasis causes an accumulation of misfolded and unfolded proteins, a condition termed ER stress. Despite advances in our understanding of the ER stress response and its downstream signaling pathway, it remains unclear how ER redox balance is controlled and restored in the stressed ER. In this study, we determined that brefeldin A (BFA)-induced protein accumulation in the ER triggers reversible oxidation of transmembrane thioredoxin-related protein 1 (TMX1). Conversion of TMX1 to the oxidized state preceded the induction of immunoglobulin-binding protein, a downstream marker of ER stress. Oxidized TMX1 reverted to the basal reduced state after BFA removal, and our results suggest that glutathione is involved in maintaining TMX1 in the reduced form. These findings provide evidence for a redox imbalance caused by protein overload, and demonstrate the existence of a pathway that helps restore ER homeostasis during poststress recovery.

SUBMITTER: Matsuo Y

PROVIDER: S-EPMC5666389 | biostudies-literature | 2017 Nov

REPOSITORIES: biostudies-literature

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Transmembrane thioredoxin-related protein TMX1 is reversibly oxidized in response to protein accumulation in the endoplasmic reticulum.

Matsuo Yoshiyuki Y Hirota Kiichi K

FEBS open bio 20171003 11

Numerous secretory and membrane proteins undergo post-translational modifications in the endoplasmic reticulum (ER), and the formation of disulfide bonds is a modification that is critical for proper protein folding. The mammalian ER contains a large family of oxidoreductases that are considered to catalyze thiol/disulfide exchange and ensure the maintenance of a redox environment within the ER. Disruption of ER homeostasis causes an accumulation of misfolded and unfolded proteins, a condition t ...[more]

PMID: 29123984

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Project description:Hundreds of tail-anchored proteins, including soluble N-ethylmaleimide-sensitive factor attachment receptors (SNAREs) involved in vesicle fusion, are inserted post-translationally into the endoplasmic reticulum membrane by a dedicated protein-targeting pathway. Before insertion, the carboxy-terminal transmembrane domains of tail-anchored proteins are shielded in the cytosol by the conserved targeting factor Get3 (in yeast; TRC40 in mammals). The Get3 endoplasmic-reticulum receptor comprises the cytosolic domains of the Get1/2 (WRB/CAML) transmembrane complex, which interact individually with the targeting factor to drive a conformational change that enables substrate release and, as a consequence, insertion. Because tail-anchored protein insertion is not associated with significant translocation of hydrophilic protein sequences across the membrane, it remains possible that Get1/2 cytosolic domains are sufficient to place Get3 in proximity with the endoplasmic-reticulum lipid bilayer and permit spontaneous insertion to occur. Here we use cell reporters and biochemical reconstitution to define mutations in the Get1/2 transmembrane domain that disrupt tail-anchored protein insertion without interfering with Get1/2 cytosolic domain function. These mutations reveal a novel Get1/2 insertase function, in the absence of which substrates stay bound to Get3 despite their proximity to the lipid bilayer; as a consequence, the notion of spontaneous transmembrane domain insertion is a non sequitur. Instead, the Get1/2 transmembrane domain helps to release substrates from Get3 by capturing their transmembrane domains, and these transmembrane interactions define a bona fide pre-integrated intermediate along a facilitated route for tail-anchor entry into the lipid bilayer. Our work sheds light on the fundamental point of convergence between co-translational and post-translational endoplasmic-reticulum membrane protein targeting and insertion: a mechanism for reducing the ability of a targeting factor to shield its substrates enables substrate handover to a transmembrane-domain-docking site embedded in the endoplasmic-reticulum membrane.

Dataset Information

Transmembrane thioredoxin-related protein TMX1 is reversibly oxidized in response to protein accumulation in the endoplasmic reticulum.

Publications

Transmembrane thioredoxin-related protein TMX1 is reversibly oxidized in response to protein accumulation in the endoplasmic reticulum.

Similar Datasets

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