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 and Shengyi Sun ()
Additional contact information
Zhenfeng Song: University of Virginia School of Medicine
Pattaraporn Thepsuwan: Wayne State University School of Medicine
Woosuk Steve Hur: 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
Juncheng Wei: Northwestern University Feinberg School of Medicine
Francesca Ferraresso: Versiti Blood Center of Wisconsin
Adrienne W. Paton: University of Adelaide
James C. Paton: University of Adelaide
Ze Zheng: Versiti Blood Center 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
Sunil Jaiman: Wayne State University School of Medicine
Matthew James Flick: University of North Carolina at Chapel Hill
Shengyi Sun: University of Virginia School of Medicine

Nature Communications, 2024, vol. 15, issue 1, 1-17

Abstract: 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.

Date: 2024
References: View references in EconPapers View complete reference list from CitEc
Citations:

Downloads: (external link)
https://www.nature.com/articles/s41467-024-53639-x Abstract (text/html)

Related works:
This item may be available elsewhere in EconPapers: Search for items with the same title.

Export reference: BibTeX RIS (EndNote, ProCite, RefMan) HTML/Text

Persistent link: https://EconPapers.repec.org/RePEc:nat:natcom:v:15:y:2024:i:1:d:10.1038_s41467-024-53639-x

Ordering information: This journal article can be ordered from
https://www.nature.com/ncomms/

DOI: 10.1038/s41467-024-53639-x

Access Statistics for this article

Nature Communications is currently edited by Nathalie Le Bot, Enda Bergin and Fiona Gillespie

More articles in Nature Communications from Nature
Bibliographic data for series maintained by Sonal Shukla () and Springer Nature Abstracting and Indexing ().