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Regulation of hepatic inclusions and fibrinogen biogenesis by SEL1L-HRD1 ERAD

Author

Listed:
  • Zhenfeng Song

    (University of Virginia School of Medicine
    Wayne State University School of Medicine)

  • Pattaraporn Thepsuwan

    (Wayne State University School of Medicine)

  • Woosuk Steve Hur

    (University of North Carolina at Chapel Hill
    University of North Carolina at Chapel Hill
    University of North Carolina at Chapel Hill)

  • Mauricio Torres

    (University of Michigan Medical School)

  • Shuangcheng Alivia Wu

    (University of Virginia School of Medicine)

  • Xiaoqiong Wei

    (University of Virginia School of Medicine)

  • Nusrat Jahan Tushi

    (University of Virginia School of Medicine
    Wayne State University School of Medicine)

  • Juncheng Wei

    (Northwestern University Feinberg School of Medicine
    Temple University)

  • Francesca Ferraresso

    (Versiti Blood Center of Wisconsin
    Medical College of Wisconsin)

  • Adrienne W. Paton

    (University of Adelaide)

  • James C. Paton

    (University of Adelaide)

  • Ze Zheng

    (Versiti Blood Center of Wisconsin
    Medical College of Wisconsin)

  • Kezhong Zhang

    (Wayne State University School of Medicine)

  • Deyu Fang

    (Northwestern University Feinberg School of Medicine)

  • Christian J. Kastrup

    (Versiti Blood Center of Wisconsin
    Medical College of Wisconsin)

  • Sunil Jaiman

    (Wayne State University School of Medicine)

  • Matthew James Flick

    (University of North Carolina at Chapel Hill
    University of North Carolina at Chapel Hill
    University of North Carolina at Chapel Hill)

  • Shengyi Sun

    (University of Virginia School of Medicine
    Wayne State University School of Medicine)

Abstract

Impaired secretion of an essential blood coagulation factor fibrinogen leads to hepatic fibrinogen storage disease (HFSD), characterized by the presence of fibrinogen-positive inclusion bodies and hypofibrinogenemia. However, the molecular mechanisms underlying the biogenesis of fibrinogen in the endoplasmic reticulum (ER) remain unexplored. Here we uncover a key role of SEL1L-HRD1 complex of ER-associated degradation (ERAD) in the formation of aberrant inclusion bodies, and the biogenesis of nascent fibrinogen protein complex in hepatocytes. Acute or chronic deficiency of SEL1L-HRD1 ERAD in the hepatocytes leads to the formation of hepatocellular inclusion bodies. Proteomics studies followed by biochemical assays reveal fibrinogen as a major component of the inclusion bodies. Mechanistically, we show that the degradation of misfolded endogenous fibrinogen Aα, Bβ, and γ chains by SEL1L-HRD1 ERAD is indispensable for the formation of a functional fibrinogen complex in the ER. Providing clinical relevance of these findings, SEL1L-HRD1 ERAD indeed degrades and thereby attenuates the pathogenicity of two disease-causing fibrinogen γ mutants. Together, this study demonstrates an essential role of SEL1L-HRD1 ERAD in fibrinogen biogenesis and provides insight into the pathogenesis of protein-misfolding diseases.

Suggested Citation

  • Zhenfeng Song & Pattaraporn Thepsuwan & Woosuk Steve Hur & Mauricio Torres & Shuangcheng Alivia Wu & Xiaoqiong Wei & Nusrat Jahan Tushi & Juncheng Wei & Francesca Ferraresso & Adrienne W. Paton & Jame, 2024. "Regulation of hepatic inclusions and fibrinogen biogenesis by SEL1L-HRD1 ERAD," Nature Communications, Nature, vol. 15(1), pages 1-17, December.
  • Handle: RePEc:nat:natcom:v:15:y:2024:i:1:d:10.1038_s41467-024-53639-x
    DOI: 10.1038/s41467-024-53639-x
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    References listed on IDEAS

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    1. Adrienne W. Paton & Travis Beddoe & Cheleste M. Thorpe & James C. Whisstock & Matthew C. J. Wilce & Jamie Rossjohn & Ursula M. Talbot & James C. Paton, 2006. "AB5 subtilase cytotoxin inactivates the endoplasmic reticulum chaperone BiP," Nature, Nature, vol. 443(7111), pages 548-552, October.
    2. 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.
    3. Xiaoqiong Wei & You Lu & Liangguang Leo Lin & Chengxin Zhang & Xinxin Chen & Siwen Wang & Shuangcheng Alivia Wu & Zexin Jason Li & Yujun Quan & Shengyi Sun & Ling Qi, 2024. "Proteomic screens of SEL1L-HRD1 ER-associated degradation substrates reveal its role in glycosylphosphatidylinositol-anchored protein biogenesis," Nature Communications, Nature, vol. 15(1), pages 1-16, December.
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