PXD029609

PXD029609 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 entry1-3. 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)4. 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	2022-09-16
AnnouncementXML	Submission_2022-09-15_16:44:02.982.xml
DigitalObjectIdentifier
ReviewLevel	Peer-reviewed dataset
DatasetOrigin	Original dataset
RepositorySupport	Unsupported dataset by repository
PrimarySubmitter	Peter Robert Mosen
SpeciesList	scientific name: Mus musculus (Mouse); NCBI TaxID: 10090;
ModificationList	S-carboxamidoethyl-L-cysteine
Instrument	Orbitrap Fusion Lumos

Revision	Datetime	Status	ChangeLog Entry
0	2021-11-08 02:50:27	ID requested
⏵ 1	2022-09-15 16:44:17	announced

Richards CM, Jabs S, Qiao W, Varanese LD, Schweizer M, Mosen PR, Riley NM, Kl, ü, ssendorf M, Zengel JR, Flynn RA, Rustagi A, Widen JC, Peters CE, Ooi YS, Xie X, Shi PY, Bartenschlager R, Puschnik AS, Bogyo M, Bertozzi CR, Blish CA, Winter D, Nagamine CM, Braulke T, Carette JE, The human disease gene LYSET is essential for lysosomal enzyme transport and viral infection. Science, 378(6615):eabn5648(2022) [pubmed]

submitter keyword: data independent acquisition (DIA), parallel reaction monitoring (PRM), targeted MS, label free quantification, mouse embryonic fibroblasts, TMEM 251

Dominic Winter
contact affiliation	Institute for Biochemistry and Molecular Biology, Medical Faculty, University of Bonn, 53115 Bonn, Germany
contact email	dominic.winter@uni-bonn.de
lab head
Peter Robert Mosen
contact affiliation	Institute of Biochemistry and Molecular Biology, University of Bonn
contact email	pmos@uni-bonn.de
dataset submitter

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PRIDE project URI

• PRIDE
  1. PXD029609
     1. Label: PRIDE project
     2. Name: The human disease gene TMEM251 is essential for lysosomal transport and viral infection