PXD029746-1

PXD029746 is an original dataset announced via ProteomeXchange.

Title	The human disease gene TMEM251 is essential for lysosomal transport and viral infection
Description	After gaining access to the endo-lysosomal pathway, several viruses depend on lysosomal cathepsin proteases to cleave their structural proteins triggering productive entry. Targeting of cathepsins and other luminal lysosomal proteins to lysosomes requires their modification with mannose 6-phosphate (M6P) signals. Key to M6P tagging is N-acetylglucosamine (GlcNAc)-1-phosphotransferase whose deficiency leads to the severe lysosomal storage disorder mucolipidosis II (MLII). Here, using genome-scale CRISPR screens, we identify the transmembrane protein TMEM251 as critically important for viral infection by cathepsin-dependent viruses including reovirus, Ebola virus, and SARS-CoV-2. We demonstrate that Golgi-resident TMEM251 is essential for lysosomal sorting and activity of cathepsins. Mechanistically, we show that TMEM251 deficiency in human cells results in global loss of M6P on luminal lysosomal proteins by destabilizing GlcNAc-1-phosphotransferase. Tmem251 knockout mice reveal characteristics typical of MLII including hypersecretion of lysosomal enzymes and accumulation of lysosomal storage material in isolated fibroblasts. Finally, we demonstrate that human pathogenic TMEM251 alleles fail to rescue lysosomal sorting defects in knockout cells. Our results uncover a crucial role of TMEM251 in M6P-dependent lysosomal transport and viral infection. Overall, work here reveals the biochemical basis of an inherited MLII-like disease caused by mutations in TMEM251 and provides insights into infection mechanisms of a broad class of medically important viruses.
HostingRepository	PRIDE
AnnounceDate	2022-09-09
AnnouncementXML	Submission_2022-09-09_10:27:24.661.xml
DigitalObjectIdentifier
ReviewLevel	Peer-reviewed dataset
DatasetOrigin	Original dataset
RepositorySupport	Unsupported dataset by repository
PrimarySubmitter	Nicholas Riley
SpeciesList	scientific name: Homo sapiens (Human); NCBI TaxID: 9606;
ModificationList	complex glycosylation
Instrument	Orbitrap Fusion

Revision	Datetime	Status	ChangeLog Entry
0	2021-11-15 06:35:05	ID requested
⏵ 1	2022-09-09 10:27:25	announced
2	2023-11-14 08:54:13	announced	2023-11-14: Updated project metadata.

10.1126/SCIENCE.ABN5648;

submitter keyword: Mannose-6-phosphate, glycoproteomics

Jan Carette
contact affiliation	Department of Microbiology and Immunology, Stanford University
contact email	carette@stanford.edu
lab head
Nicholas Riley
contact affiliation	Stanford University
contact email	riley.nicholasm@gmail.com
dataset submitter

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PRIDE project URI

• PRIDE
  1. PXD029746
     1. Label: PRIDE project
     2. Name: The human disease gene TMEM251 is essential for lysosomal transport and viral infection