{"type": "root", "children": [{"type": "p", "children": [{"type": "t", "text": "\nLYSET, also known as TMEM251, is a Golgi-resident transmembrane protein that plays a critical role in the lysosomal enzyme trafficking pathway. It associates with GlcNAc-1-phosphotransferase, the enzyme responsible for adding mannose-6-phosphate (M6P) tags to soluble hydrolases in the Golgi apparatus. This M6P modification is essential for targeting these enzymes to lysosomes, ensuring proper degradation of extracellular and autophagic cargoes."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "1"}]}, {"type": "t", "text": ""}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nLoss of LYSET function disrupts this critical process: in the absence of LYSET, GlcNAc-1-phosphotransferase becomes unstable and is mislocalized from the Golgi to lysosomes. Consequently, there is a global loss of M6P tagging which leads to depletion of lysosomal enzymes and severely impairs the turnover of macropinocytic and autophagic substrates. The resulting lysosomal dysfunction not only underlies the pathomechanism of severe lysosomal storage disorders resembling mucolipidosis II but also impacts cellular adaptation processes, including metabolic strategies in cancer and susceptibility to viral infections that depend on cathepsin activity."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "1"}, {"type": "fg_f", "ref": "3"}]}, {"type": "t", "text": ""}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nCollectively, these findings establish LYSET as a core component required for the retention and proper function of the GlcNAc-1-phosphotransferase complex in the Golgi apparatus, and consequently, for efficient lysosomal enzyme trafficking. Inherited mutations disrupting LYSET function can result in severe lysosomal storage phenotypes, highlighting its potential as a therapeutic target for disorders associated with impaired lysosomal degradation and metabolic adaptations in cancer."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "3"}]}, {"type": "t", "text": ""}]}, {"type": "rg", "children": [{"type": "r", "ref": 1, "children": [{"type": "t", "text": "Christopher M Richards, Sabrina Jabs, Wenjie Qiao, et al. "}, {"type": "b", "children": [{"type": "t", "text": "The human disease gene LYSET is essential for lysosomal enzyme transport and viral infection."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Science (2022)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1126/science.abn5648"}], "href": "https://doi.org/10.1126/science.abn5648"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "36074821"}], "href": "https://pubmed.ncbi.nlm.nih.gov/36074821"}]}, {"type": "r", "ref": 2, "children": [{"type": "t", "text": "Catarina Pechincha, Sven Groessl, Robert Kalis, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Lysosomal enzyme trafficking factor LYSET enables nutritional usage of extracellular proteins."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Science (2022)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1126/science.abn5637"}], "href": "https://doi.org/10.1126/science.abn5637"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "36074822"}], "href": "https://pubmed.ncbi.nlm.nih.gov/36074822"}]}, {"type": "r", "ref": 3, "children": [{"type": "t", "text": "Wenjie Qiao, Christopher M Richards, Sabrina Jabs "}, {"type": "b", "children": [{"type": "t", "text": "LYSET/TMEM251- a novel key component of the mannose 6-phosphate pathway."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Autophagy (2023)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1080/15548627.2023.2167376"}], "href": "https://doi.org/10.1080/15548627.2023.2167376"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "36633450"}], "href": "https://pubmed.ncbi.nlm.nih.gov/36633450"}]}]}]}