PXD039061-1

PXD039061 is an original dataset announced via ProteomeXchange.

Title	The p97-UBXD8 complex regulates ER-Mitochondria contact sites by altering membrane lipid saturation and composition
Description	The intimate association between the endoplasmic reticulum (ER) and mitochondrial membranes at ER-mitochondria contact sites (ERMCS) serves as a platform for several critical cellular processes, particularly lipid synthesis. How contacts are remodeled and the subsequent biological consequences of altered contacts such as perturbed lipid metabolism remains poorly understood. Here we show that the p97 AAA-ATPase and its ER-tethered ubiquitin-X domain adaptor 8 (UBXD8) regulate the prevalence of ERMCS. The p97-UBXD8 complex localizes to contacts and its loss increases contacts in a manner that is dependent on p97 catalytic activity. Quantitative proteomics and lipidomics of ERMCS demonstrates alterations in proteins regulating lipid metabolism and a significant change in saturated or monounsaturated lipid species in UBXD8 knockout cells. We show that loss of p97-UBXD8 results in perturbed contacts due to an increase in membrane lipid saturation via SREBP1 and the lipid desaturase SCD1. These aberrant contacts can be rescued by supplementation with unsaturated fatty acids or overexpression of SCD1. Notably, we find that the SREBP1-SCD1 pathway is negatively impacted in the brains of mice with p97 mutations that cause neurodegeneration. Our results suggest that contacts are exquisitely sensitive to alterations to membrane lipid composition and saturation in a p97-UBXD8 dependent manner.
HostingRepository	PRIDE
AnnounceDate	2023-01-25
AnnouncementXML	Submission_2023-01-25_09:23:21.490.xml
DigitalObjectIdentifier
ReviewLevel	Peer-reviewed dataset
DatasetOrigin	Original dataset
RepositorySupport	Unsupported dataset by repository
PrimarySubmitter	JoaoPaulo
SpeciesList	scientific name: Homo sapiens (Human); NCBI TaxID: 9606;
ModificationList	iodoacetamide derivatized residue
Instrument	Orbitrap Fusion Lumos

Revision	Datetime	Status	ChangeLog Entry
0	2022-12-22 02:24:47	ID requested
⏵ 1	2023-01-25 09:23:21	announced

Dataset with its publication pending

submitter keyword: SREBP1,ERMCS, SCD1, UBXD8, neurodegeneration

MalavikaRaman
contact affiliation	Department of Developmental Molecular and Chemical Biology Tufts University School of Medicine Boston MA
contact email	malavika.raman@tufts.edu
lab head
JoaoPaulo
contact affiliation	Harvard Medical School
contact email	joao_paulo@post.harvard.edu
dataset submitter

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PRIDE project URI

• PRIDE
  1. PXD039061
     1. Label: PRIDE project
     2. Name: The p97-UBXD8 complex regulates ER-Mitochondria contact sites by altering membrane lipid saturation and composition