Lysosomal enzyme trafficking factor LYSET enables nutritional usage of extracellular proteins

Science. 2022 Oct 7;378(6615):eabn5637. doi: 10.1126/science.abn5637. Epub 2022 Oct 7.


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.

MeSH terms

  • Animals
  • Golgi Apparatus* / metabolism
  • Humans
  • Lysosomal Storage Diseases* / genetics
  • Lysosomal Storage Diseases* / metabolism
  • Lysosomes* / metabolism
  • Mice
  • Protein Transport
  • Proteins* / genetics
  • Proteins* / metabolism
  • Transferases (Other Substituted Phosphate Groups) / genetics
  • Transferases (Other Substituted Phosphate Groups) / metabolism


  • LYSET protein, human
  • Proteins
  • Transferases (Other Substituted Phosphate Groups)
  • GNPTAB protein, human
  • GNPTG protein, human