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

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) remains unexplored. Here we uncovered 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. Serendipitously, acute or chronic deficiency of SEL1L-HRD1 ERAD, but not UPR sensor IRE1α, in the hepatocytes led to the formation of hepatocellular inclusion bodies. Proteomics studies followed by biochemical assays revealed fibrinogen, not albumin or α1-antitrypsin, as a major component of the inclusion bodies. Degradation of misfolded endogenous fibrinogen Aα, Bβ, and γ chains by SEL1L-HRD1 ERAD was required for the formation of a functional fibrinogen complex in the ER. Providing clinical relevance of these findings, SEL1L-HRD1 ERAD indeed degraded and thereby attenuated the pathogenicity of a disease-causing fibrinogen γ mutant. Together, this study demonstrates an essential role of SEL1L-HRD1 ERAD in fibrinogen biogenesis and provides novel insights into the pathogenesis of protein-misfolding diseases.

INSTRUMENT(S): Q Exactive HF

ORGANISM(S): Mus Musculus (mouse)

TISSUE(S): Liver

SUBMITTER: Xiaoqiong Wei

LAB HEAD: Shengyi Sun

PROVIDER: PXD047658 | Pride | 2024-09-11

REPOSITORIES: Pride

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	PRF-2021-L-QI-584_PRF_Q_2021_L_QI_584_50909_50912_original.xlsx	Xlsx
	PRF_Q_2021_L_QI_584_50909.msf	Msf
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	PRF_Q_2021_L_QI_584_50910.msf	Msf
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