PXD048503

PXD048503 is an original dataset announced via ProteomeXchange.

Title	ERLIN1 and ERLIN2 scaffolds bridge TMUB1 and RNF170 and restrict cholesterol esterification to regulate the secretory pathway
Description	Complexes of ERLIN1 and ERLIN2 form large ring-like cup shaped structures on the endoplasmic reticulum (ER) membrane and serve as platform to bind cholesterol and E3-ubiquitin ligases, potentially defining functional nanodomains. Here, we show that ERLIN scaffolds mediate the interaction between the full-length isoform of TMUB1 and RNF170. We identify a luminal N-terminal conserved region in TMUB1 and RNF170 required for the interaction. Three-dimensional modelling using Alpha Fold Multimer shows that this conserved motif binds the SPFH domain of two adjacent ERLIN subunits at different interfaces. ERLIN1 and ERLIN2 variants that preclude these interactions are unstable and have been previously linked to hereditary spastic paraplegia (HSP), a progressive neurological disorder. Using HeLa cells that lack both ERLINs, we uncovered novel processes dependent on these scaffolds. Proteomics and lipidomics approaches demonstrated a role of ERLINs in cell adhesion, vesicular secretion, and cholesterol and sphingomyelin metabolism. Cells lacking ERLINs displayed collapsed tubular ER, a fragmented Golgi apparatus, and impaired post-Golgi trafficking. Moreover, they accumulated cholesterol esters and triacylglycerols in larger lipid droplets. We found that inhibition of sterol-O-acyltransferase 1 with avasimibe suppressed lipid droplet accumulation, Golgi fragmentation and SREBP activation. We conclude that ERLIN scaffolds maintain cholesterol levels at the ER in check by favouring trafficking to the Golgi over esterification, thereby regulating the secretory pathway.
HostingRepository	PRIDE
AnnounceDate	2024-05-21
AnnouncementXML	Submission_2024-05-21_02:40:35.652.xml
DigitalObjectIdentifier
ReviewLevel	Peer-reviewed dataset
DatasetOrigin	Original dataset
RepositorySupport	Unsupported dataset by repository
PrimarySubmitter	Prerana Wagle
SpeciesList	scientific name: Homo sapiens (Human); NCBI TaxID: 9606;
ModificationList	monohydroxylated residue; iodoacetamide derivatized residue
Instrument	Q Exactive Plus

Revision	Datetime	Status	ChangeLog Entry
0	2024-01-12 04:49:27	ID requested
⏵ 1	2024-05-21 02:40:36	announced

Dataset with its publication pending

submitter keyword: ERLIN2, TMUB1, DRMs, endoplasmic reticulum, Hereditary Spastic Paraplegia,ERLIN1, lipid rafts

Elena I. Rugarli
contact affiliation	CECAD Research Center, Joseph-Stelzmann Str. 26, 50931, Cologne, Germany
contact email	Elena.rugarli@uni-koeln.de
lab head
Prerana Wagle
contact affiliation	CECAD Research Center
contact email	proteomics-facility@uni-koeln.de
dataset submitter

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PRIDE project URI

• PRIDE
  1. PXD048503
     1. Label: PRIDE project
     2. Name: ERLIN1 and ERLIN2 scaffolds bridge TMUB1 and RNF170 and restrict cholesterol esterification to regulate the secretory pathway