LYSET (lysosomal enzyme trafficking factor) encodes a transmembrane protein essential for lysosomal enzyme transport via the mannose 6-phosphate (M6P) pathway 1. LYSET localizes to the Golgi apparatus where it directly interacts with GlcNAc-1-phosphotransferase (GNPT), the enzyme responsible for M6P tagging of lysosomal hydrolases 12. This interaction is critical for GNPT stability and activity, as LYSET deficiency results in global loss of M6P tagging and mislocalization of GNPT from Golgi to lysosomes 1. The protein's Golgi retention is maintained by GOLPH3/GOLPH3L adaptors, which ensure proper localization of the LYSET-GNPT complex 3. LYSET is particularly important for cellular utilization of extracellular proteins through macropinocytosis, as LYSET-deficient cells show impaired turnover of macropinocytic and autophagic cargoes 2. Pathogenic LYSET variants cause a mucolipidosis II-like disorder characterized by dysostosis multiplex and lysosomal storage defects 14. Additionally, LYSET is essential for viral infections that depend on cathepsins, including SARS-CoV-2, making it a potential antiviral target 15.