Lysosomal enzyme trafficking factor LYSET enables nutritional usage of extracellular proteins

Mammalian cells can generate amino acids through macropinocytosis and lysosomal breakdown of extracellular proteins, which is exploited by cancer cells to grow in nutrient-poor tumors. Through genetic screens in defined nutrient conditions, we characterized LYSET, a transmembrane protein (TMEM251) selectively required when cells consume extracellular proteins. LYSET was found to associate in the Golgi with GlcNAc-1-phosphotransferase, which targets catabolic enzymes to lysosomes through mannose-6-phosphate modification. Without LYSET, GlcNAc-1-phosphotransferase was unstable because of a hydrophilic transmembrane domain. Consequently, LYSET-deficient cells were depleted of lysosomal enzymes and impaired in turnover of macropinocytic and autophagic cargoes. Thus, LYSET represents a core component of the lysosomal enzyme trafficking pathway, underlies the pathomechanism for hereditary lysosomal storage disorders, and may represent a target to suppress metabolic adaptations in cancer.

Automated summary

Mammalian cells can generate amino acids through macropinocytosis and lysosomal breakdown of extracellular proteins, which cancer cells exploit for growth in nutrient-poor tumors. In this study, a transmembrane protein called LYSET was found to be selectively required for the consumption of extracellular proteins. LYSET is associated with GlcNAc-1-phosphotransferase in the Golgi, which targets catabolic enzymes to lysosomes. LYSET deficiency leads to a depletion of lysosomal enzymes and impairs the turnover of macropinocytic and autophagic cargoes.