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Vertebrate cells rely on mannose-6-phosphate (M6P) modifications to deliver most lumenal hydrolases to the lysosome. As a critical trafficking signal for lysosomal enzymes, the M6P biosynthetic pathway has been thoroughly investigated. However, its regulatory mechanism is largely unknown. Here, we summarize three recent studies that independently discovered LYSET/TMEM251/GCAF as a key regulator of the M6P pathway. LYSET/TMEM251 directly interacts with GNPT, the enzyme that catalyzes the transfer of M6P, and is critical for its activity and stability. Deleting  LYSET/TMEM251  impairs the GNPT function and M6P modifications. Consequently, lysosomal enzymes are mistargeted for secretion. Defective lysosomes fail to degrade cargoes such as endocytic vesicles and autophagosomes, leading to a newly identified lysosomal storage disease in humans. These discoveries open up a new direction in the regulation of the M6P biosynthetic pathway. Abbreviations:  ER: endoplasmic reticulum; GNPT: GlcNAc-1-phosphotransferase; KO: knockout; LMP: lysosome membrane protein; LYSET: lysosomal enzyme trafficking factor; MAP1LC3/LC3: microtubule-associated protein 1 light chain 3; M6P: mannose-6-phosphate; MBTPS1/S1P: membrane-bound transcription factor peptidase, site 1; MPR: mannose-6-phosphate receptor; SQSTM1: sequestosome 1; TEM: transmission electron microscopy; TGN: trans-Golgi network.

LYSET/TMEM251/GCAF is critical for autophagy and lysosomal function by regulating the mannose-6-phosphate (M6P) pathway