PXD047658-2

PXD047658 is an original dataset announced via ProteomeXchange.

Title	Regulation of hepatic inclusions and fibrinogen biogenesis by SEL1L-HRD1 ERAD
Description	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.
HostingRepository	PRIDE
AnnounceDate	2024-10-22
AnnouncementXML	Submission_2024-10-22_06:57:59.929.xml
DigitalObjectIdentifier
ReviewLevel	Peer-reviewed dataset
DatasetOrigin	Original dataset
RepositorySupport	Unsupported dataset by repository
PrimarySubmitter	Xiaoqiong Wei
SpeciesList	scientific name: Mus musculus (Mouse); NCBI TaxID: 10090;
ModificationList	No PTMs are included in the dataset
Instrument	Q Exactive HF

Revision	Datetime	Status	ChangeLog Entry
0	2023-12-08 10:18:53	ID requested
1	2024-09-11 12:29:00	announced
⏵ 2	2024-10-22 06:58:00	announced	2024-10-22: Updated project metadata.

Dataset with its publication pending

submitter keyword: hepatocytes,SEL1L-HRD1 ERAD, fibrinogen, inclusion bodies

Shengyi Sun
contact affiliation	Department of Pharmacology, University of Virginia School of Medicine, Charlottesville, Virginia 22908, USA
contact email	bjk5fz@virginia.edu
lab head
Xiaoqiong Wei
contact affiliation	University of Michigan
contact email	weixi@umich.edu
dataset submitter

Dataset FTP location NOTE: Most web browsers have now discontinued native support for FTP access within the browser window. But you can usually install another FTP app (we recommend FileZilla) and configure your browser to launch the external application when you click on this FTP link. Or otherwise, launch an app that supports FTP (like FileZilla) and use this address: ftp://ftp.pride.ebi.ac.uk/pride/data/archive/2024/09/PXD047658

PRIDE project URI

• PRIDE
  1. PXD047658
     1. Label: PRIDE project
     2. Name: Regulation of hepatic inclusions and fibrinogen biogenesis by SEL1L-HRD1 ERAD