Regulation of hepatic inclusions and fibrinogen biogenesis by SEL1L-HRD1 ERAD
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.
Authors
- Kezhong Zhang (ORCID: https://orcid.org/0000-0002-6062-235X)
- Matthew J. Flick (ORCID: https://orcid.org/0000-0002-5034-3162)
- Mauricio Torres (ORCID: https://orcid.org/0000-0002-5081-9044)
- Christian J. Kastrup (ORCID: https://orcid.org/0000-0003-3644-0019)
- Shengyi Sun (ORCID: https://orcid.org/0000-0002-1734-3902)
- Francesca Ferraresso
- Xiaoqiong Wei (ORCID: https://orcid.org/0000-0001-7576-4820)
- Adrienne W. Paton (ORCID: https://orcid.org/0000-0002-2996-5733)
- Deyu Fang (ORCID: https://orcid.org/0000-0002-4211-2751)
- Woosuk S. Hur (ORCID: https://orcid.org/0000-0001-5074-6423)
- Pattaraporn Thepsuwan (ORCID: https://orcid.org/0000-0002-8046-8548)
- James C. Paton (ORCID: https://orcid.org/0000-0001-9807-5278)
- Juncheng Wei (ORCID: https://orcid.org/0000-0001-5262-477X)
- Shuangcheng Alivia Wu (ORCID: https://orcid.org/0000-0002-2289-7141)
- Ze Zheng (ORCID: https://orcid.org/0000-0002-9676-2856)
- Zhenfeng Song (ORCID: https://orcid.org/0000-0002-3026-1987)
- Sunil Jaiman
- Nusrat Jahan Tushi
Institutions
- Northwestern University (US)
- University of North Carolina at Chapel Hill (US)
- University of North Carolina Health Care (US)
- Wayne State University (US)
- Medical College of Wisconsin (US)
- University of Michigan (US)
- Versiti Blood Center of Wisconsin (US)
- University of Virginia (US)
- The University of Adelaide (AU)
- Temple University (US)
Publication Details
- Journal
- Nature Communications
- Published
- 2024-10-25
- DOI
- https://doi.org/10.1038/s41467-024-53639-x
- Citations
- 11
- Primary Topic
- Endoplasmic Reticulum Stress and Disease
- Type
- article
- Field-Weighted Citation Impact
- 3.59
Funders
- American Society of Nephrology
- National Heart, Lung, and Blood Institute
- National Institute of Diabetes and Digestive and Kidney Diseases
- Eunice Kennedy Shriver National Institute of Child Health and Human Development