Which signal is necessary for targeting soluble lysosomal enzymes?
Among diverse sorting determinants mannose-6-phosphate uniquely marks entire class of soluble lysosomal precursors enabling intracellular lysosome biogenesis. Newly synthesized acid hydrolases enter ER lumen, receive high-mannose N-glycans via oligosaccharyltransferase, fold with calnexin, move to cis-Golgi where Golgi-resident phosphotransferase adds M6P as phosphodiester then uncovered in TGN to yield exposed phosphate. Carbohydrate address recognized in TGN pH 6.7 by two M6P receptors both P-type lectins: 300 kDa cation-independent IGF2 receptor binding also IGF2 and 46 kDa cation-dependent requiring divalent cation. Receptors cluster via cytosolic motifs YXXPhi and DXXLL binding AP1 and GGA recruiting clathrin lattice. KDEL retrieval maintains ER chaperones BiP via KDEL receptor and COPI, DXE mediates ER exit for membrane cargo via Sec24 COPII, NPXY plus AP2 handles plasma membrane endocytosis via ARH co-adaptor. Without M6P addition or receptor, lysosomal enzymes follow default secretion to extracellular medium. Experimental addition exogenous M6P competes for receptor binding abolishing sorting confirming receptor-ligand nature essential for lysosome formation and cell physiology.
Ref: Lodish et al., MCB: Mannose-6-phosphate signal targets soluble lysosomal enzymes to lysosomes.