8.A.208.  The Lysosomal Enzyme Trafficking Factor (LYSET) Family

LYSET (TMEM251) family proteins include enzyme trafficking and nutrient usage of extracellular proteins (Pechincha et al. 2022). The human disease gene LYSET is essential for lysosomal enzyme transport and viral infection (Richards et al. 2022). Mammalian cells can generate amino acids through macropinocytosis and lysosomal breakdown of extracellular proteins. It is required for mannose-6-phosphate-dependent trafficking of lysosomal enzymes (Pechincha et al. 2022; Zhang et al. 2022. LYSET bridges GlcNAc-1-phosphate transferase (GNPTAB), to the membrane-bound transcription factor site-1 protease (MBTPS1), thus allowing proteolytic activation of the GNPTAB. GNPTAB is involved in the regulation of M6P-dependent Golgi-to-lysosome trafficking of lysosomal enzymes (Zhang et al. 2022). LYSET is thus an essential factor for maturation and delivery of lysosomal hydrolases (Pechincha et al. 2022). For example, LYSET is required for correct functioning of the M6P trafficking machinery and mutations in LYSET can explain the phenotype of the associated disorder (Richards et al. 2022).