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PGRMC1 acts as a size-selective cargo receptor to drive ER-phagic clearance of mutant prohormones

Author

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  • Yu-Jie Chen

    (University of Michigan Medical School)

  • Jeffrey Knupp

    (University of Michigan Medical School
    Cellular and Molecular Biology Program, University of Michigan Medical School)

  • Anoop Arunagiri

    (Division of Metabolism Endocrinology & Diabetes, University of Michigan Medical School)

  • Leena Haataja

    (Division of Metabolism Endocrinology & Diabetes, University of Michigan Medical School)

  • Peter Arvan

    (Cellular and Molecular Biology Program, University of Michigan Medical School
    Division of Metabolism Endocrinology & Diabetes, University of Michigan Medical School)

  • Billy Tsai

    (University of Michigan Medical School
    Cellular and Molecular Biology Program, University of Michigan Medical School)

Abstract

The reticulon-3 (RTN3)-driven targeting complex promotes clearance of misfolded prohormones from the endoplasmic reticulum (ER) for lysosomal destruction by ER-phagy. Because RTN3 resides in the cytosolic leaflet of the ER bilayer, the mechanism of selecting misfolded prohormones as ER-phagy cargo on the luminal side of the ER membrane remains unknown. Here we identify the ER transmembrane protein PGRMC1 as an RTN3-binding partner. Via its luminal domain, PGRMC1 captures misfolded prohormones, targeting them for RTN3-dependent ER-phagy. PGRMC1 selects cargos that are smaller than the large size of other reported ER-phagy substrates. Cargos for PGRMC1 include mutant proinsulins that block secretion of wildtype proinsulin through dominant-negative interactions within the ER, causing insulin-deficiency. Chemical perturbation of PGRMC1 partially restores WT insulin storage by preventing ER-phagic degradation of WT and mutant proinsulin. Thus, PGRMC1 acts as a size-selective cargo receptor during RTN3-dependent ER-phagy, and is a potential therapeutic target for diabetes.

Suggested Citation

  • Yu-Jie Chen & Jeffrey Knupp & Anoop Arunagiri & Leena Haataja & Peter Arvan & Billy Tsai, 2021. "PGRMC1 acts as a size-selective cargo receptor to drive ER-phagic clearance of mutant prohormones," Nature Communications, Nature, vol. 12(1), pages 1-17, December.
    • Handle: RePEc:nat:natcom:v:12:y:2021:i:1:d:10.1038_s41467-021-26225-8
    DOI: 10.1038/s41467-021-26225-8
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    References listed on IDEAS

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    1. Miao Wang & Randal J. Kaufman, 2016. "Protein misfolding in the endoplasmic reticulum as a conduit to human disease," Nature, Nature, vol. 529(7586), pages 326-335, January.
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    1. Shuangcheng Alivia Wu & Chenchen Shen & Xiaoqiong Wei & Xiawei Zhang & Siwen Wang & Xinxin Chen & Mauricio Torres & You Lu & Liangguang Leo Lin & Huilun Helen Wang & Allen H. Hunter & Deyu Fang & Shen, 2023. "The mechanisms to dispose of misfolded proteins in the endoplasmic reticulum of adipocytes," Nature Communications, Nature, vol. 14(1), pages 1-17, December.

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