Regulation of hepatic inclusions and fibrinogen biogenesis by SEL1L-HRD1 ERAD. Nat Commun 2024 Oct 26;15(1):9244
Date
10/26/2024Pubmed ID
39455574Pubmed Central ID
PMC11512042DOI
10.1038/s41467-024-53639-xScopus ID
2-s2.0-85207624408 (requires institutional sign-in at Scopus site)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 List
Song Z, Thepsuwan P, Hur WS, Torres M, Wu SA, Wei X, Tushi NJ, Wei J, Ferraresso F, Paton AW, Paton JC, Zheng Z, Zhang K, Fang D, Kastrup CJ, Jaiman S, Flick MJ, Sun SAuthors
Christian Kastrup PhD Professor in the Surgery department at Medical College of WisconsinZe Zheng PhD Assistant Professor in the Medicine department at Medical College of Wisconsin
MESH terms used to index this publication - Major topics in bold
AfibrinogenemiaAnimals
Endoplasmic Reticulum
Endoplasmic Reticulum-Associated Degradation
Fibrinogen
HEK293 Cells
Hepatocytes
Humans
Inclusion Bodies
Liver
Male
Mice
Mice, Inbred C57BL
Mice, Knockout
Protein Folding
Proteins
Ubiquitin-Protein Ligases
