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

Zhenfeng Song; Pattaraporn Thepsuwan; Woosuk Steve Hur; Mauricio Torres; Shuangcheng Alivia Wu; Xiaoqiong Wei; Nusrat Jahan Tushi; Juncheng Wei; Francesca Ferraresso; Adrienne W. Paton; James C. Paton; Ze Zheng; Kezhong Zhang; Deyu Fang; Christian J. Kastrup; Sunil Jaiman; Matthew James Flick; Shengyi Sun

doi:10.1038/s41467-024-53639-x

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

Zhenfeng Song, Pattaraporn Thepsuwan, Woosuk Steve Hur, Mauricio Torres, Shuangcheng Alivia Wu, Xiaoqiong Wei, Nusrat Jahan Tushi, Juncheng Wei, Francesca Ferraresso, Adrienne W. Paton, James C. Paton, Ze Zheng, Kezhong Zhang, Deyu Fang, Christian J. Kastrup, Sunil Jaiman, Matthew James Flick, Shengyi Sun^*

^*Corresponding author for this work

Pathology

Research output: Contribution to journal › Article › peer-review

2 Scopus citations

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.

Original language	English (US)
Article number	9244
Journal	Nature communications
Volume	15
Issue number	1
DOIs	https://doi.org/10.1038/s41467-024-53639-x
State	Published - Dec 2024

Funding

We thank Drs. Yuan Zhang, David J. Mangelsdorf and Steven A. Kliewer for sharing reagents; Drs. James P. Luyendyk, Alisa S. Wolberg, Lih Jiin Juang, Ling Qi, and members of the Sun laboratories for their insightful discussions. We also thank the University of Virginia Advanced Microscopy Facility, Wayne State University Microscopy, Imaging and Cytometry Resources Core, Michigan Diabetes Research Center, University of Michigan In-vivo Animal Core, and Vector Core for their support. This work was supported by the funding from NIH (R01DK132068 and R01DK128077 to SS; R01HL160046 to MJF; R01HL166382 to CJK; R01DK120330 and R01DK126908 to DF; DK090313 and R01DK126908 to KZ; R01HL163516 to ZZ; and R21HD104904 to JW), American Society of Nephrology (XW), and National Health and Medical Research Council Investigator Grant 1174876 (JCP).

ASJC Scopus subject areas

General Chemistry
General Biochemistry, Genetics and Molecular Biology
General Physics and Astronomy

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Song, Z., Thepsuwan, P., Hur, W. S., Torres, M., Wu, S. A., Wei, X., Tushi, N. J., Wei, J., Ferraresso, F., Paton, A. W., Paton, J. C., Zheng, Z., Zhang, K., Fang, D., Kastrup, C. J., Jaiman, S., Flick, M. J., & Sun, S. (2024). Regulation of hepatic inclusions and fibrinogen biogenesis by SEL1L-HRD1 ERAD. Nature communications, 15(1), Article 9244. https://doi.org/10.1038/s41467-024-53639-x

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title = "Regulation of hepatic inclusions and fibrinogen biogenesis by SEL1L-HRD1 ERAD",

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.",

author = "Zhenfeng Song and Pattaraporn Thepsuwan and Hur, {Woosuk Steve} and Mauricio Torres and Wu, {Shuangcheng Alivia} and Xiaoqiong Wei and Tushi, {Nusrat Jahan} and Juncheng Wei and Francesca Ferraresso and Paton, {Adrienne W.} and Paton, {James C.} and Ze Zheng and Kezhong Zhang and Deyu Fang and Kastrup, {Christian J.} and Sunil Jaiman and Flick, {Matthew James} and Shengyi Sun",

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doi = "10.1038/s41467-024-53639-x",

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AU - Song, Zhenfeng

AU - Thepsuwan, Pattaraporn

AU - Hur, Woosuk Steve

AU - Torres, Mauricio

AU - Wu, Shuangcheng Alivia

AU - Wei, Xiaoqiong

AU - Tushi, Nusrat Jahan

AU - Wei, Juncheng

AU - Ferraresso, Francesca

AU - Paton, Adrienne W.

AU - Paton, James C.

AU - Zheng, Ze

AU - Zhang, Kezhong

AU - Fang, Deyu

AU - Kastrup, Christian J.

AU - Jaiman, Sunil

AU - Flick, Matthew James

AU - Sun, Shengyi

PY - 2024/12

Y1 - 2024/12

N2 - 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.

AB - 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.

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

Abstract

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