The human disease gene LYSET is essential for lysosomal enzyme transport and viral infection
作者：Christopher M. Richards, Sabrina Jabs, Wenjie Qiao, Lauren D. Varanese, Michaela Schweizer , et al.
Science：2022/09/08
Lysosomes are key degradative compartments of the cell. Transport to lysosomes relies on GlcNAc-1-phosphotransferase–mediated tagging of soluble enzymes with mannose 6-phosphate (M6P). GlcNAc-1-phosphotransferase deficiency leads to the severe lysosomal storage disorder mucolipidosis II (MLII). Several viruses require lysosomal cathepsins to cleave structural proteins and thus depend on functional GlcNAc-1-phosphotransferase. We used genome-scale CRISPR screens to identify lysosomal enzyme trafficking factor (LYSET, also named TMEM251) as essential for infection by cathepsin-dependent viruses including severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). LYSET deficiency resulted in global loss of M6P tagging and mislocalization of GlcNAc-1-phosphotransferase from the Golgi complex to lysosomes. Lyset knockout mice exhibited MLII-like phenotypes, and human pathogenic LYSET alleles failed to restore lysosomal sorting defects. Thus, LYSET is required for correct functioning of the M6P trafficking machinery and mutations in LYSET can explain the phenotype of the associated disorder.
（导读 领研网）溶酶体是细胞中至关重要的的降解区室。本研究使用基因组尺度的CRISPR筛查确定了溶酶体酶转运因子（LYSET）对依赖组织蛋白酶的病毒的感染至关重要。LYSET的缺乏导致M6P标记的全面丧失和GlcNAc-1磷酸转移酶从高尔基体到溶酶体的错误定位。LYSET为M6P转运机制正确运行所必需，而LYSET突变可解释相关疾病表型。
