Module 18: Lysosomes and Malaria (PDF)

MODULE 18 Sorting Proteins at TGN receptor-mediated sorting: lysosomal hydrolases via M6P receptor to the lysosome via endosomes; another type of sorting is via sortilin and clathrin to endosomes sorting of proteins for secretory vesicles: the molecules aggregate in the presence of...

MODULE 18 Sorting Proteins at TGN receptor-mediated sorting: lysosomal hydrolases via M6P receptor to the lysosome via endosomes; another type of sorting is via sortilin and clathrin to endosomes sorting of proteins for secretory vesicles: the molecules aggregate in the presence of low pH and Ca2+, condense/mature from immature (ISG) to mature storage granules (MSG) CARTS transport Lysosome C and PAUF to the cell surface Unknown Mechanisms Lysosomal Proteins at TGN mannose-6-phosphates (M6P) on lysosomal enzymes are recognized by M6P receptors (MPRs) enzymes are transported from TGN in clathrin vesicles to endosomes and later, to lysosomes MPRs are also on the plasma membrane to capture escaped (secreted) enzymes and return them to lysosomes lysosomal proteins are synthesized on ER-bound ribosomes Lysosomes membrane-enclosed organelles, acidic pH, with proton pumps moving protons inside contain enzymes (acid hydrolases) with mannose-6-phosphate tags, recognized by MPRs clathrin-coated sections bud off enclosing the enzymes and their receptors clathrin is lost, the vesicle fuses with an endosome, where the low pH releases the enzymes from their receptors Lysosomal Trafficking vesicle formation starts with the recruitment of the small GTPase ARF1 clathrin-coated vesicles from TGN contain GGA, an adaptor protein GGA binds ARF proteins, clathrin, and the cytosolic tails of membrane proteins (bound to cargo), including MPRs the interactions concentrate the MPRs in clathrin-coated vesicles after budding from TGN, the clathrin coat is removed from the vesicles Proton (H+) Pumps optimal pH for acid hydrolases is 4.6; it is maintained by H+-ATPase pumps the inner side of the lysosomal membrane is shielded by highly glycosylated integral membrane proteins MODULE 18 Lysosomes and Malaria four species of Plasmodium parasites cause most malaria cases in humans flu-like symptoms coincide with the increasing number of parasites in the bloodstream; later onset of febrile attacks in absence of treatment, malaria is chronic chloroquine targets the food vacuole (lysosome) of Plasmodium by increasing its pH and inactivating the lysosomal acid hydrolases Lysosomal Storage Disorders deficiencies in lysosomal enzymes lead to the accumulation of undegraded substrates genetic disorders, ~40-50 lysosomal storage disorders mostly affect the nervous system Tay-Sachs: a deficiency in hexosaminidase A, accumulation of ganglioside GM2, which is a major component of brain cell membranes; death by around age three I-cell Disease psychomotor retardation; skeletal deformities lysosomes contain undigested glycosaminoglycans and glycolipids approximately eight acid hydrolases are secreted instead of being packaged into lysosomes caused by phosphotransferase deficiency (the first step in adding the phospho-group to mannose is not accomplished) Niemann-Pick Type C Disease accumulation of cholesterol and glycolipids in the lysosomes due to mutant NPC1 or NPC2 protein NPC1 functions as a transporter in the endosomal-lysosomal system Summary – Intracellular Transport sorting of proteins from the TGN occurs through receptor-mediated sorting, soluble protein sorting via sortilin/clathrin to lysosomes, storage granules for secretion, CARTS to the cell surface, and other mechanisms to the apical and basolateral surfaces (focus on the first two mechanisms) lysosomes contain acid hydrolases that function in an acidic environment (pH 4.6-5.0) defects in lysosomal acid hydrolases or other lysosomal proteins may result in lysosomal storage diseases, where the accumulation of macromolecules causes cellular damage, often resulting in death at a young age