LYSET/TMEM251/GCAF is critical for autophagy and lysosomal function by regulating the mannose-6-phosphate (M6P) pathway.
LYSET/TMEM251/GCAF is critical for autophagy and lysosomal function by regulating the mannose-6-phosphate (M6P) pathway.
复制标题
LYSET/TMEM251/GCAF 通过调节 6-磷酸甘露糖 (M6P) 途径对自噬和溶酶体功能至关重要。
DOI：
10.1080/15548627.2023.2167375
复制
发表时间：
2023
期刊：
影响因子：
13.3
通讯作者：
Li,Ming
中科院分区：
文献类型：
--
作者：
Zhang,Bokai;Yang,Xi;Li,Ming
脊椎动物细胞依赖于甘露糖-6-磷酸（M6 P）修饰来将大多数内腔水解酶递送至溶酶体。作为溶酶体酶的关键运输信号，M6 P生物合成途径已被彻底研究。然而，其调节机制在很大程度上是未知的。在这里，我们总结了最近的三项研究，独立发现LYSET/TMEM 251/GCAF作为M6 P通路的关键调节因子。LYSET/TMEM 251直接与催化M6 P转移的酶GNPT相互作用，并且对其活性和稳定性至关重要。删除LYSET/TMEM 251会损害GNPT功能和M6 P修饰。因此，溶酶体酶被错误地定位为分泌。有缺陷的溶酶体不能降解货物，如内吞囊泡和自噬体，导致一种新发现的人类溶酶体贮积病。缩写：ER：内质网; GNPT：GlcNAc-1-磷酸转移酶; KO：敲除; LMP：溶酶体膜蛋白; LYSET：溶酶体酶运输因子; MAP 1 LC 3/LC 3：微管相关蛋白1轻链3; M6 P：甘露糖-6-磷酸; MBTPS 1/S1 P：膜结合转录因子肽酶，位点1; MPR：甘露糖-6-磷酸受体; SQSTM 1：螯合体1; TEM：透射电子显微镜; TGN：trans-Golgi网络
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. DeletingLYSET/TMEM251impairs 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.