The Human Disease Gene LYSET is Essential for Lysosomal Enzyme Transport and Viral Infection

ABSTRACT: Lysosomes are key degradative compartments of the cell. Transport to lysosomes ismediated by tagging soluble enzymes with mannose 6-phosphate (M6P) by GlcNAc-1-phosphotransferase whose deficiency leads to the severe lysosomal storage disorder mucolipidosisII (MLII). Several viruses require lysosomal cathepsins to cleave structural proteins and thusdepend on functional GlcNAc-1-phosphotransferase. Using genome-scale CRISPR screens, weidentify LYSET as essential for infection by cathepsin-dependent viruses including SARS-CoV-2. We show that LYSET deficiency results in global loss of M6P tagging and mislocalization ofGlcNAc-1-phosphotransferase to lysosomes. Lyset knockout mice exhibit MLII-like phenotypesand human pathogenic LYSET alleles fail to restore lysosomal sorting defects. Thus, we uncoverLYSET as an indispensable component of the M6P trafficking machinery and reveal thebiochemical basis of an inherited disease caused by mutations in LYSET.

INSTRUMENT(S): Orbitrap Fusion Lumos

ORGANISM(S): Mus Musculus (mouse)

TISSUE(S): Fibroblast

DISEASE(S): Disease Free

SUBMITTER: Peter Robert Mosen  

LAB HEAD: Dominic Winter

PROVIDER: PXD029609 | Pride | 2022-09-15

REPOSITORIES: Pride