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A subset of UPR-induced transmembrane proteins are prematurely degraded during lipid perturbation

View ORCID ProfileBenjamin S.H. Ng, View ORCID ProfilePeter Shyu Jr., View ORCID ProfileNurulain Ho, Ruijie Chaw, Seah Yi Ling, View ORCID ProfileGuillaume Thibault
doi: https://doi.org/10.1101/178947
Benjamin S.H. Ng
School of Biological Sciences, Nanyang Technological University, Singapore, 637551
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Peter Shyu Jr.
School of Biological Sciences, Nanyang Technological University, Singapore, 637551
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Nurulain Ho
School of Biological Sciences, Nanyang Technological University, Singapore, 637551
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Ruijie Chaw
School of Biological Sciences, Nanyang Technological University, Singapore, 637551
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Seah Yi Ling
School of Biological Sciences, Nanyang Technological University, Singapore, 637551
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Guillaume Thibault
School of Biological Sciences, Nanyang Technological University, Singapore, 637551
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ABSTRACT

Background Phospholipid homeostasis in biological membranes is essential to maintain functions of organelles such as the endoplasmic reticulum. Phospholipid perturbation has been associated to non-alcoholic fatty liver disease, obesity and other metabolic disorders. However, in most cases, the biological significance of lipid disequilibrium remains unclear. Previously, we reported that Saccharomyces cerevisiae adapts to lipid disequilibrium by upregulating several protein quality control pathways such as the endoplasmic reticulum-associated degradation (ERAD) pathway and the unfolded protein response (UPR).

Results Surprisingly, we observed certain ER-resident transmembrane proteins (TPs), which form part of the UPR programme, to be destabilised under lipid perturbation (LP). Among these, Sbh1 was prematurely degraded by fatty acid remodelling and membrane stiffening of the ER. Moreover, the protein translocon subunit Sbh1 is targeted for degradation through its transmembrane domain in an unconventional Doa10-dependent manner.

Conclusion Premature removal of key ER-resident TPs might be an underlying cause of chronic ER stress in metabolic disorders.

  • LIST OF ABBREVIATIONS

    co-IP
    co-immunoprecipitation
    CytoQC
    cytosolic protein quality control
    DMPE
    N-dimethyl phosphatidylethanolamine
    ER
    endoplasmic reticulum
    ERAD
    endoplasmic reticulum-associated degradation
    FA
    fatty acid
    LP
    lipid perturbation
    MMPE
    N-monomethyl phosphatidylethanolamine
    MYTH
    membrane yeast two hybrid
    NAFLD
    non-alcoholic fatty liver disease
    NASH
    non-alcoholic steatohepatitis
    PC
    phosphatidylcholine
    PE
    phosphatidylethanolamine
    SERCA
    sarco/endoplasmic reticulum Ca2+-ATPase
    T2D
    type II diabetes
    TP
    transmembrane protein
    UPR
    unfolded protein response
  • Copyright 
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    Posted June 11, 2018.
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    A subset of UPR-induced transmembrane proteins are prematurely degraded during lipid perturbation
    Benjamin S.H. Ng, Peter Shyu Jr., Nurulain Ho, Ruijie Chaw, Seah Yi Ling, Guillaume Thibault
    bioRxiv 178947; doi: https://doi.org/10.1101/178947
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    A subset of UPR-induced transmembrane proteins are prematurely degraded during lipid perturbation
    Benjamin S.H. Ng, Peter Shyu Jr., Nurulain Ho, Ruijie Chaw, Seah Yi Ling, Guillaume Thibault
    bioRxiv 178947; doi: https://doi.org/10.1101/178947

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