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PXD046335-1

PXD046335 is an original dataset announced via ProteomeXchange.

Dataset Summary
TitleThe fatty liver disease-causing protein PNPLA3-I148M alters lipid droplet-Golgi dynamics
DescriptionNon-alcoholic fatty liver disease (NAFLD), recently renamed metabolic dysfunction-associated steatotic liver disease (MASLD), is a progressive metabolic disorder that begins with aberrant triglyceride accumulation in the liver and can lead to cirrhosis and cancer. A common variant in the gene PNPLA3, encoding the protein PNPLA3-I148M, is the strongest known genetic risk factor for MASLD to date. Despite its discovery twenty years ago, the function of PNPLA3, and now the role of PNPLA3-I148M, remain unclear. In this study, we sought to dissect the biogenesis of PNPLA3 and PNPLA3-I148M and characterize changes induced by endogenous expression of the disease-causing variant. Contrary to bioinformatic predictions and prior studies with overexpressed proteins, we demonstrate here that PNPLA3 and PNPLA3-I148M are not endoplasmic reticulum-resident transmembrane proteins. To identify their intracellular associations, we generated a paired set of isogenic human hepatoma cells expressing PNPLA3 and PNPLA3-I148M at endogenous levels. Both proteins were enriched in lipid droplet, Golgi, and endosomal fractions. Purified PNPLA3 and PNPLA3-I148M proteins associated with phosphoinositides commonly found in these compartments. Despite a similar fractionation pattern as the wild-type variant, PNPLA3-I148M induced morphological changes in the Golgi apparatus, including increased lipid droplet-Golgi contact sites, which were also observed in I148M-expressing primary human patient hepatocytes. In addition to lipid droplet accumulation, PNPLA3-I148M expression caused significant proteomic and transcriptomic changes that resembled all stages of liver disease. Cumulatively, we validate an endogenous human cellular system for investigating PNPLA3-I148M biology and identify the Golgi apparatus as a central hub of PNPLA3-I148M-driven cellular change.
HostingRepositoryPRIDE
AnnounceDate2024-04-10
AnnouncementXMLSubmission_2024-04-09_19:21:41.315.xml
DigitalObjectIdentifier
ReviewLevelPeer-reviewed dataset
DatasetOriginOriginal dataset
RepositorySupportUnsupported dataset by repository
PrimarySubmitterBrett Lomenick
SpeciesList scientific name: Homo sapiens (Human); NCBI TaxID: 9606;
ModificationListphosphorylated residue; acetylated residue; monohydroxylated residue; iodoacetamide derivatized residue
InstrumentOrbitrap Eclipse
Dataset History
RevisionDatetimeStatusChangeLog Entry
02023-10-23 13:46:51ID requested
12024-04-09 19:21:41announced
Publication List
Dataset with its publication pending
Keyword List
submitter keyword: endosome, MASLD, Golgi,liver disease, PNPLA3, lipid droplet, NAFLD
Contact List
Tsui-Fen Chou
contact affiliationProteome Exploration Laboratory, California Institute of Technology, Pasadena, CA 91125, USA
contact emailtfchou@caltech.edu
lab head
Brett Lomenick
contact affiliationUCLA
contact emailblomenick@ucla.edu
dataset submitter
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Dataset FTP location
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