PDF(Pubmed)
Abstract：
Degradation of macromolecules delivered to lysosomes by processes such as autophagy or endocytosis is crucial for cellular function. Lysosomes require more than 60 soluble hydrolases in order to catabolize such macromolecules. These soluble hydrolases are tagged with mannose6-phosphate (M6P) moieties in sequential reactions by the Golgi-resident GlcNAc-1-phosphotransferase complex and NAGPA/UCE/uncovering enzyme (N-acetylglucosamine-1-phosphodiester alpha-N-acetylglucosaminidase), which allows their delivery to endosomal/lysosomal compartments through trafficking mediated by cation-dependent and -independent mannose 6-phosphate receptors (MPRs). We and others recently identified TMEM251 as a novel regulator of the M6P pathway via independent genome-wide genetic screening strategies. We renamed TMEM251 to LYSET (lysosomal enzyme trafficking factor) to establish nomenclature reflective to this gene\'s function. LYSET is a Golgi-localized transmembrane protein important for the retention of the GlcNAc-1-phosphotransferase complex in the Golgi-apparatus. The current understanding of LYSET\'s importance regarding human biology is 3-fold: 1) highly pathogenic viruses that depend on lysosomal hydrolase activity require LYSET for infection. 2) The presence of LYSET is critical for cancer cell proliferation in nutrient-deprived environments in which extracellular proteins must be catabolized. 3) Inherited pathogenic alleles of LYSET can cause a severe inherited disease which resembles GlcNAc-1-phosphotransferase deficiency (i.e., mucolipidosis type II).Abbreviations: GlcNAc-1-PT: GlcNAc-1-phosphotransferase; KO: knockout; LSD: lysosomal storage disorder; LYSET: lysosomal enzyme trafficking factor; M6P: mannose 6-phosphate; MPRs: mannose-6-phosphate receptors, cation-dependent or -independent; MBTPS1/site-1 protease: membrane bound transcription factor peptidase, site 1; MLII: mucolipidosis type II; WT: wild-type.
摘要：
通过自噬或内吞等过程降解递送到溶酶体的大分子对于细胞功能至关重要。溶酶体需要超过60种可溶性水解酶以分解代谢此类大分子。这些可溶性水解酶在高尔基体驻留的GlcNAc-1-磷酸转移酶复合物和NAGPA/UCE/揭开酶（N-乙酰葡糖胺-1-磷酸二酯α-N-乙酰葡糖胺糖苷酶）的连续反应中被甘露糖-6-磷酸（M6P）部分标记，这允许它们通过由阳离子依赖性和非依赖性甘露糖-6-磷酸受体（MPR）介导的运输递送到内体/溶酶体区室。我们和其他人最近通过独立的全基因组遗传筛选策略将TMEM251鉴定为M6P途径的新型调节因子。我们将TMEM251重命名为LYSET（溶酶体酶运输因子），以建立反映该基因功能的命名法。LYSET是高尔基体定位的跨膜蛋白，对于在高尔基体中保留GlcNAc-1-磷酸转移酶复合物很重要。目前对LYSET在人类生物学方面的重要性的理解是3倍：1）依赖于溶酶体水解酶活性的高致病性病毒需要LYSET进行感染。2)在营养缺乏的环境中,LYSET的存在对于癌细胞增殖是关键的,其中细胞外蛋白必须被分解代谢。3）LYSET的遗传致病性等位基因可引起类似GlcNAc-1-磷酸转移酶缺乏症的严重遗传性疾病（即，II型粘脂症）。
