Lecture 1 - Introduction to Lysosomes and Their Role in Infections Flashcards
What are the implications of multicellularity?
Specialisation, division of labour
What are the advantages of compartmentalisation?
Efficiency, different environments/conditions/pH
What are the disadvantages of compartmentalisation?
Energy input/resources needed to maintain ordered structure, regulatory mechanisms needed
What are lysosomes?
Single membrane-bound organelles containing more than 50 acid hydrolyses that function in the degradation of macromolecules for various purposes.
e.g. hydrolyse proteins, DNA, RNA, polysaccharides and lipids
e.g. autophagy or endocytosis and phagocytosis
Why are lysosomes morphologically diverse organelles?
They can display considerable variation in size and shape as a result of differences in the materials that have been taken up for digestion
They are defined by the common function of degrading intracellular material
What are lysosomal storage diseases?
Mutations in the genes that encode these enzymes are responsible for more than 30 different human genetic diseases, which are called lysosomal storage diseases.
This is due to un-degraded materials accumulating within the lysosomes of affected individuals.
Most of these diseases result from deficiencies in single lysosomal enzymes.
Eg, Gaucher’s disease (the most common of these disorders) - a mutation in the gene that encodes a lysosomal enzyme
required for the breakdown of glycolipids.
V-ATPases are large, multisubunit complexes. What are they composed of?
- Each V-ATPase is composed of:
- a peripheral ATP hydrolytic domain and
- an integral proton-translocation domain that operates by a rotary mechanism.
However, unlike the F-ATPases, the V-ATPases do not function under physiological conditions to synthesize ATP from ADP and phosphate.
What is required for the generation and maintenance of the extremely acidic luminal pH?
- V-ATPase pump
- other ion-transport processes to prevent the buildup of a prohibitive electrical potential across the phagosomal membrane.
+ The inward flux of anions (mainly Cl—),
+ The efflux of cations (probably K+ and Na+) through conductive pathways, neutralizes the electrogenic effect of the V-ATPase
How do researchers visualise the low pH environment in lysosomes?
LysoTracker - weakly basic amines selectively accumulate in cellular components with low internal pH and can be used to investigate the biosynthesis and pathogenesis of lysosomes
How does a phagolysosome form?
Lysosome fuses with late phagosome
How is phagocytosis described?
Phagocytosis is a receptor-mediated process through which macrophages ingest large particulate antigens (>=0.5 pm) from the outside of the cell into a membrane bound vacuole termed the phagosome.
This requires remodelling of the plasma membrane with the aid of the actin cytoskeleton
- Extension of pseudopod to surround the microorganism to internalise it.
What type of immunity are phagocytes involved in?
Innate immunity
Phagocytes such as macrophages and neutrophils take up bacterial and fungal pathogens.
How does phagosome maturation occur in phagocytes during activation of innate immunity?
- The nascent phagosome undergoes significant biochemical remodeling revealed by the acquisition and removal of proteins and a marked drop in pH.
- Phagosome formation in and of itself is not microbicidal because the lumen of the nascent vacuole is similar to the fluid phase outside the macrophage and the phagosomal membrane is derived directly from the plasma membrane.
How are early phagosomes, late phagosomes, and phagolosyosomes defined/differentiated?
The presence of specific markers aid in defining the state of phagosome maturation.
Low pH in phagolysosome
Cathepsin D - major lysosomal asartic proteinase, activated in low pH
Other than acid hydrolases, how are microbes killed within phagolysosomes?
Other proteins and enzymes
- NADPH oxidase - generate reactive oxygen species (ROS)
- O2 dismutate to H2O2, react with O2 to generate hydroxyl radicals and singlet oxygen
- iNOS (inducible nitric oxide synthase) helps generate NO that reacts with ROS to give rise to reactive nitrogen species (RNS)
- Lactoferrin - chelates ferric ions and reduces availability to micro-organisms
