PXD046335-1

PXD046335 is an original dataset announced via ProteomeXchange.

Title	The fatty liver disease-causing protein PNPLA3-I148M alters lipid droplet-Golgi dynamics
Description	Non-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.
HostingRepository	PRIDE
AnnounceDate	2024-04-10
AnnouncementXML	Submission_2024-04-09_19:21:41.315.xml
DigitalObjectIdentifier
ReviewLevel	Peer-reviewed dataset
DatasetOrigin	Original dataset
RepositorySupport	Unsupported dataset by repository
PrimarySubmitter	Brett Lomenick
SpeciesList	scientific name: Homo sapiens (Human); NCBI TaxID: 9606;
ModificationList	phosphorylated residue; acetylated residue; monohydroxylated residue; iodoacetamide derivatized residue
Instrument	Orbitrap Eclipse

Revision	Datetime	Status	ChangeLog Entry
0	2023-10-23 13:46:51	ID requested
⏵ 1	2024-04-09 19:21:41	announced

Dataset with its publication pending

submitter keyword: endosome, MASLD, Golgi,liver disease, PNPLA3, lipid droplet, NAFLD

Tsui-Fen Chou
contact affiliation	Proteome Exploration Laboratory, California Institute of Technology, Pasadena, CA 91125, USA
contact email	tfchou@caltech.edu
lab head
Brett Lomenick
contact affiliation	UCLA
contact email	blomenick@ucla.edu
dataset submitter

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PRIDE project URI

• PRIDE
  1. PXD046335
     1. Label: PRIDE project
     2. Name: The fatty liver disease-causing protein PNPLA3-I148M alters lipid droplet-Golgi dynamics