Question

The principal pathway for transport of lysosomal hydrolases from the trans Golgi network (pH 6.6) to the late endosomes (pH 6) and for the recycling of M6P receptors back to the Golgi depends on the pH difference between these two compartments. From what you know about M6P receptor binding and recycling and the pathways for delivery of material to lysosomes, describe the consequences of changing the pH in those two compartments.

A.   What do you suppose would be the fate of the M6P receptors and the hydrolases if the pH in the late endosomes where raised to pH 6.6?

B.   What do you suppose would be the fate of the M6P receptors and the hydrolases if the pH in the trans Golgi network were lowered to pH 6?

Answer 1

Ans A) We know that mannose-6-phosphate (M6P) residues bind to mannose-6-phosphate receptors (M6P) present on the trans-Golgi network. The clathrin/API coated vesicles having M6P receptor and hydrolases (lysosomal enzymes) bud from the trnas-Golgi network and fuse to the late endosomes (which has pH of ~5.5 i.e more acidic). But, M6P receptors can only bind M6P at only slightly acidic pH (within the range of 6.5 - 7).So,what happens is, late endosomes will release some of its bound lysosomal enzymes like hydrolases to make pH slightly acidic.

Thus, if the pH is raised to 6.6, M6P receptors will remain bound to M6P and no cargo will be dumped in the late endosome.

Ans B) If the pH is lowered to 6, M6P receptors can no longer bind to M6P (as discussed above, MGP receptors can only bind to M6P at slightly acidic pH i.e 6.5 - 7) and dump the cargo in the late endosome.These vesicles later bud from late endosomes and fuse with lysosomes to deliver hydrolases. And,the free M6P receptors will get recycled to trans-Golgi network for the next round to begin.