LYSET, also named TMEM251, is a Golgi-localized transmembrane protein essential for the correct functioning of the mannose 6-phosphate (M6P) trafficking machinery [3,4]. This machinery is crucial for transporting soluble hydrolases to lysosomes, and lysosomes rely on these hydrolases to degrade macromolecules delivered through various routes. LYSET associates with GlcNAc-1-phosphotransferase in the Golgi, which tags lysosomal enzymes with M6P for their proper trafficking [2]. It has significant biological importance in processes such as viral infection, cancer cell metabolism, and prevention of lysosomal storage disorders [3].

LYSET-knockout mice exhibited mucolipidosis II (MLII)-like phenotypes, indicating that LYSET is required for the normal function of the M6P trafficking machinery [1]. LYSET deficiency led to global loss of M6P tagging and mislocalization of GlcNAc-1-phosphotransferase from the Golgi complex to lysosomes [1]. Also, human pathogenic LYSET alleles failed to restore lysosomal sorting defects [1]. In addition, LYSET-deficient cells were depleted of lysosomal enzymes and impaired in the turnover of macropinocytic and autophagic cargoes, highlighting its role in the nutritional usage of extracellular proteins [2].

In conclusion, LYSET is a core component of the lysosomal enzyme trafficking pathway. Its function, as revealed through gene-knockout mouse models, is essential for maintaining proper lysosomal function. Mutations in LYSET can lead to MLII-like phenotypes, and LYSET also plays a role in viral infection and cancer cell metabolism, providing potential therapeutic targets in these disease areas.