Seo Jinho, Oh Doo-Byoung
Environmental Disease Research Center, Korea Research Institute of Bioscience and Biotechnology (KRIBB), Daejeon, Korea.
Department of Biosystems and Bioengineering, KRIBB School of Biotechnology, University of Science and Technology (UST), Daejeon, Korea.
Anim Cells Syst (Seoul). 2022 May 29;26(3):84-91. doi: 10.1080/19768354.2022.2079719. eCollection 2022.
A lysosome, an acidic membrane-bound organelle, contains hydrolytic enzymes to digest macromolecules for recycling. Many lysosomal enzymes (LEs) traffic to the lysosome through the mannose-6-phosphate (M6P)-dependent pathway. Some mannose residues of high-mannose type -glycans on LEs can be phosphorylated in the Golgi apparatus through two-step enzyme reactions. The consequent M6P moiety is recognized by M6P receptors (MPRs) on the -Golgi network membrane and delivered through the endo-lysosomal pathway. On the other hand, secreted LEs containing M6P glycans can be recaptured by MPRs on the plasma membrane and targeted to the lysosome. Enzyme replacement therapy (ERT) for lysosomal storage diseases exploits this M6P-MPR-dependent endocytosis to deliver recombinant enzymes to lysosomes. This review discusses various engineering and application technologies using M6P's lysosomal targeting. Glyco-engineering for increasing M6P contents developed 'Bio-better' ERT enzymes with enhanced therapeutic efficacy. M6P-decorated peptides, proteins, liposomes, and nanoparticles have been developed for drug delivery and subcellular imaging. A recently developed lysosome-targeting chimera uses an M6P-based bifunctional binder to degrade specific extracellular and membrane proteins. The success and efficiency of M6P-based lysosomal targeting will boost further technological developments with new applications in the biomedical field.
溶酶体是一种酸性的膜结合细胞器，含有水解酶以消化大分子进行循环利用。许多溶酶体酶（LEs）通过依赖于甘露糖-6-磷酸（M6P）的途径运输到溶酶体。LEs上高甘露糖型聚糖的一些甘露糖残基可在高尔基体中通过两步酶促反应被磷酸化。由此产生的M6P部分被高尔基体网络膜上的M6P受体（MPRs）识别，并通过内溶酶体途径传递。另一方面，含有M6P聚糖的分泌型LEs可被质膜上的MPRs重新捕获并靶向溶酶体。溶酶体贮积症的酶替代疗法（ERT）利用这种依赖于M6P-MPR的内吞作用将重组酶递送至溶酶体。本文综述了利用M6P溶酶体靶向的各种工程和应用技术。增加M6P含量的糖工程开发出了具有增强治疗效果的“生物改良型”ERT酶。已开发出用M6P修饰的肽、蛋白质、脂质体和纳米颗粒用于药物递送和亚细胞成像。最近开发的一种溶酶体靶向嵌合体使用基于M6P的双功能结合剂来降解特定的细胞外和膜蛋白。基于M6P的溶酶体靶向的成功和效率将推动生物医学领域新应用的进一步技术发展。
