脊椎动物细胞依赖于甘露糖-6-磷酸(M6P)修饰以将大多数腔水解酶递送至溶酶体。作为溶酶体酶的关键运输信号,M6P生物合成途径已被彻底研究。然而,其调控机制在很大程度上是未知的。这里,我们总结了最近三项独立发现LYSET/TMEM251/GCAF作为M6P通路的关键调节因子的研究。LYSET/TMEM251直接与GNPT交互,催化M6P转移的酶,对其活性和稳定性至关重要。删除LYSET/TMEM251会损害GNPT功能和M6P修改。因此,溶酶体酶的分泌被误用。有缺陷的溶酶体不能降解货物,如内吞囊泡和自噬体,导致人类新发现的溶酶体贮积病。这些发现为M6P生物合成途径的调控开辟了新的方向。
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.