Writing in Science, two independent studies use genetic screens to identify a membrane protein that plays an essential role in trafficking of lysosomal proteases into the lysosome, and thereby influences the ability of the lysosome to perform its various functions. The two groups renamed this protein (originally called TMEM251) as lysosomal enzyme trafficking factor, or LYSET.
Pechincha et al. (Science https://doi.org/10.1126/science.abn5637; 2022) used pancreatic adenocarcinoma cells to identify genes that are required for the acquisition of amino-acid nutrients through catabolism of extracellular proteins in the lysosome, which commonly occurs in nutrient-deficient milieus — for example, in the microenvironments of tumors. To enforce this pathway, Pechincha et al. deprived the cells of essential amino acids and instead provided serum protein albumin as an amino-acid source. The authors then used a CRISPR–Cas9 screen to search for genes that are needed for the intact function of this lysosomal catabolic pathway. Their screen identified LYSET as an essential player in this pathway. Using fluorescently labelled albumin to trace its fate after its uptake into the cell, they found that LYSET is needed for lysosomal degradation of endocytosed albumin. They then investigated changes in cellular proteomic signatures following knockout of the LYSET gene. Although this did not significantly alter the general constituents of the proteome, they observed a marked mistrafficking of lysosomal enzymes to the cell surface. This correlated with a loss of the mannose-6-phosphate (M6P) post-translational modification on lysosomal enzymes — a mark that is needed for the efficient targeting of these enzymes for uptake into the lysosome where they perform their catabolic functions.
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