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

Autor: Song Z; Department of Pharmacology, University of Virginia School of Medicine, Charlottesville, VA, 22908, USA.; Center for Molecular Medicine and Genetics, Wayne State University School of Medicine, Detroit, MI, 48201, USA., Thepsuwan P; Center for Molecular Medicine and Genetics, Wayne State University School of Medicine, Detroit, MI, 48201, USA., Hur WS; Department of Pathology and Laboratory Medicine, University of North Carolina at Chapel Hill, Chapel Hill, NC, 27514, USA.; Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, NC, 27514, USA.; UNC Blood Research Center, University of North Carolina at Chapel Hill, Chapel Hill, NC, 27514, USA., Torres M; Department of Molecular & Integrative Physiology, University of Michigan Medical School, Ann Arbor, MI, 48105, USA., Wu SA; Department of Molecular Physiology and Biological Physics, University of Virginia School of Medicine, Charlottesville, VA, 22908, USA., Wei X; Department of Molecular Physiology and Biological Physics, University of Virginia School of Medicine, Charlottesville, VA, 22908, USA., Tushi NJ; Department of Pharmacology, University of Virginia School of Medicine, Charlottesville, VA, 22908, USA.; Center for Molecular Medicine and Genetics, Wayne State University School of Medicine, Detroit, MI, 48201, USA., Wei J; Department of Pathology, Northwestern University Feinberg School of Medicine, Chicago, IL, 60611, USA.; Department of Cardiovascular Sciences and Center for Metabolic Disease Research, Lewis Katz School of Medicine, Temple University, Philadelphia, PA, USA., Ferraresso F; Blood Research Institute, Versiti Blood Center of Wisconsin, Milwaukee, WI, 53226, USA.; Departments of Surgery, Biochemistry, Biomedical Engineering, and Pharmacology and Toxicology, Medical College of Wisconsin, Milwaukee, WI, 53226, USA., Paton AW; Research Centre for Infectious Diseases, Department of Molecular and Biomedical Science, University of Adelaide, Adelaide, South Australia, 5005, Australia., Paton JC; Research Centre for Infectious Diseases, Department of Molecular and Biomedical Science, University of Adelaide, Adelaide, South Australia, 5005, Australia., Zheng Z; Blood Research Institute, Versiti Blood Center of Wisconsin, Milwaukee, WI, 53226, USA.; Department of Medicine, Medical College of Wisconsin, Milwaukee, WI, 53226, USA., Zhang K; Center for Molecular Medicine and Genetics, Wayne State University School of Medicine, Detroit, MI, 48201, USA., Fang D; Department of Pathology, Northwestern University Feinberg School of Medicine, Chicago, IL, 60611, USA., Kastrup CJ; Blood Research Institute, Versiti Blood Center of Wisconsin, Milwaukee, WI, 53226, USA.; Departments of Surgery, Biochemistry, Biomedical Engineering, and Pharmacology and Toxicology, Medical College of Wisconsin, Milwaukee, WI, 53226, USA., Jaiman S; Department of Pathology, Wayne State University School of Medicine, Detroit, MI, 48201, USA., Flick MJ; Department of Pathology and Laboratory Medicine, University of North Carolina at Chapel Hill, Chapel Hill, NC, 27514, USA.; Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, NC, 27514, USA.; UNC Blood Research Center, University of North Carolina at Chapel Hill, Chapel Hill, NC, 27514, USA., Sun S; Department of Pharmacology, University of Virginia School of Medicine, Charlottesville, VA, 22908, USA. bjk5fz@virginia.edu.; Center for Molecular Medicine and Genetics, Wayne State University School of Medicine, Detroit, MI, 48201, USA. bjk5fz@virginia.edu.
Jazyk: angličtina
Zdroj: Nature communications [Nat Commun] 2024 Oct 26; Vol. 15 (1), pp. 9244. Date of Electronic Publication: 2024 Oct 26.
DOI: 10.1038/s41467-024-53639-x
Abstrakt: 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.
(© 2024. The Author(s).)
Databáze: MEDLINE
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