biostudies-literatureSong ZU.S. Department of Health & Human Services | NIH | Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD)American Society of NephrologyNIDDK NIH HHSNHLBI NIH HHSU.S. Department of Health & Human Services | NIH | National Institute of Diabetes and Digestive and Kidney Diseases (National Institute of Diabetes & Digestive & Kidney Diseases)U.S. Department of Health & Human Services | NIH | National Heart, Lung, and Blood InstituteNCI NIH HHSU.S. Department of Health & Human Services | NIH | National Heart, Lung, and Blood Institute (NHLBI)U.S. Department of Health & Human Services | NIH | Eunice Kennedy Shriver National Institute of Child Health and Human DevelopmentU.S. Department of Health & Human Services | NIH | National Institute of Diabetes and Digestive and Kidney Diseases9244https://www.ebi.ac.uk/biostudies/studies/S-EPMC11512042biostudies-literatureUnknown15(1)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. MechanisticaNature communicationsRegulation of hepatic inclusions and fibrinogen biogenesis by SEL1L-HRD1 ERAD.PMC11512042DK090313R01 HL168009R01DK128077R01 DK090313R01DK132068R01DK126908R21HD104904R01HL166382R01HL163516R01 DK126908U01 CA274304Thepsuwan PZheng ZTorres MZhang KFang DKastrup CJWei XTushi NJPaton JCWu SAPaton AWJaiman SHur WSFlick MJFerraresso FSun SWei JSong ZfalseRegulation 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. Mechanistica2024-01-01T00:00:00Z2024 Oct2026-06-02T23:27:40.721Z2025-04-06T03:14:00.943ZS-EPMC115120423945557410.1038/s41467-024-53639-x