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人类疾病基因LYSET对溶酶体酶的运输和病毒感染至关重要
作者:小柯机器人 发布时间:2022/9/11 21:46:31

美国斯坦福大学Jan E. Carette、德国汉堡大学Thomas Braulke等研究人员合作发现,人类疾病基因LYSET对溶酶体酶的运输和病毒感染至关重要。2022年9月8日,国际知名学术期刊《科学》在线发表了这一成果。

研究人员表示,溶酶体是细胞的关键降解区室。向溶酶体运输依赖于GlcNAc-1-磷酸转移酶介导的具有6-磷酸甘露糖(M6P)标记的可溶性酶。GlcNAc-1-磷酸转移酶的缺乏导致了严重的溶酶体储存障碍粘脂症II(MLII)。一些病毒需要溶酶体组织蛋白酶来切割结构蛋白,因此依赖于功能性GlcNAc-1-磷酸转移酶。

研究人员使用基因组规模的CRISPR筛选,确定溶酶体酶运输因子(LYSET)对依赖猫蛋白酶的病毒(包括SARS-CoV-2)的感染至关重要。LYSET的缺乏导致M6P标签的全面丧失和GlcNAc-1-磷酸转移酶从高尔基复合体到溶酶体的错误定位。Lyset敲除小鼠表现出类似MLII的表型,人类致病的LYSET等位基因未能恢复溶酶体分选缺陷。因此,LYSET是M6P运输机制正确运作所需的,而LYSET的突变可以解释相关疾病的表型。

附:英文原文

Title: The human disease gene LYSET is essential for lysosomal enzyme transport and viral infection

Author: Christopher M. Richards, Sabrina Jabs, Wenjie Qiao, Lauren D. Varanese, Michaela Schweizer, Peter R. Mosen, Nicholas M. Riley, Malte Klüssendorf, James R. Zengel, Ryan A. Flynn, Arjun Rustagi, John C. Widen, Christine E. Peters, Yaw Shin Ooi, Xuping Xie, Pei-Yong Shi, Ralf Bartenschlager, Andreas S. Puschnik, Matthew Bogyo, Carolyn R. Bertozzi, Catherine A. Blish, Dominic Winter, Claude M. Nagamine, Thomas Braulke, Jan E. Carette

Issue&Volume: 2022-09-08

Abstract: 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. Here, we used genome-scale CRISPR screens to identify Lysosomal Enzyme Trafficking factor (LYSET) as essential for infection by cathepsin-dependent viruses including 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.

DOI: abn5648

Source: https://www.science.org/doi/10.1126/science.abn5648

 

期刊信息
Science:《科学》,创刊于1880年。隶属于美国科学促进会,最新IF:41.037