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#cellular digestion

2 public questions tagged with this topic.

Cell Organelles

Which lysosomal membrane protein is required for fusion with phagosomes?

Phagosome maturation in macrophages and neutrophils converts a nascent bacteria-containing vacuole into a microbicidal phagolysosome through sequential interactions with early endosomes, late endosomes and terminal lysosomes. Acquisition of lysosomal membrane proteins marks progression, with lysosome-associated membrane proteins 1 and 2, LAMP1 and LAMP2, being the most abundant heavily glycosylated proteins delivered to maturing phagosomes, protecting membrane from hydrolases. Studies using LAMP-1 and LAMP-2 knockout mice and combined siRNA show single loss causes mild delay while double deficiency impairs recruitment of Rab7 GTPase, loss of early marker EEA1 and failure of lysosomes to fuse, indicating cooperative requirement for tethering and SNARE complex assembly alongside syntaxin 7 and VAMP8. Additionally, phagosome resolution into lysosome-derived vesicles depends on clathrin coats, actin polymerization via Arp2/3 and microtubule motors that fragment the vacuole after cargo degradation, recycling membrane for reuse. Clathrin adaptors AP1 and EpsinR also deliver lysosomal phosphatases via Rab5 early endosomes to expand phagocytic cup. Thus both structural LAMP proteins and clathrin-mediated membrane remodeling cooperate sequentially in phagolysosome formation and turnover for host defense.

Ref: Huynh et al., EMBO Journal 2007: LAMP Proteins Are Required for Fusion of Lysosomes with Phagosomes.

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Cell Organelles

The acidic pH of lysosomes is maintained by:

Lysosomes maintain a highly acidic lumen essential for optimal activity of about sixty acid hydrolases involved in macromolecular digestion and for solute transport. The steep proton gradient, pH 4.5 to 5.0 inside versus cytosolic pH 7.2, representing over two pH units and hundredfold proton concentration difference, is actively generated by vacuolar-type H+ ATPase, V-ATPase, consuming ATP. This massive multi-subunit rotary pump consists of peripheral V1 domain with A3B3 hexamer that hydrolyzes ATP and integral V0 domain forming proton channel with c-ring rotation. ATP hydrolysis drives rotation of central stalk and c-ring, translocating protons into the lumen against electrochemical gradient at cost of one ATP per two to three protons. Counterion movement of chloride via ClC-7 Cl-/H+ exchanger and potassium channel provides electroneutrality and osmotic balance preventing excessive membrane potential. Resulting acidity activates cathepsins B, D, L and others by protonation of catalytic residues, induces conformational changes releasing enzymes from mannose-6-phosphate receptors after delivery, and denatures substrates improving access. Low pH also prevents hydrolase leakage from causing cytosolic damage. Inhibition by bafilomycin A1 or concanamycin neutralizes lysosomes, blocking degradation, autophagy flux, and cholesterol egress from NPC1 pathway.

Ref: Alberts et al., Molecular Biology of the Cell, 6th ed., Chapter 13: Lysosomes – V-ATPase and Acidification.

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