Endocytosis II

  • Pathways Taken by Endocytosed Cargo

    • Pathway 1: LDL (Low-Density Lipoproteins)

    • Related to atherosclerosis, heart attacks, strokes

    • Pathway 2: EGF and TGF (Growth Factors)

    • Important in cancer mechanisms

    • Pathway 3: Transferrin (Iron transport)

    • Pathway 4: Transcytosis of Immunoglobulins

    • Pathway 5: Endothelial transcytosis

    • Pathway 6: Phagocytosis (to be covered later)

  • Pathway 1: Endocytosis of LDL

    • LDL binds to its receptor on the plasma membrane

    • Internalized via clathrin-mediated endocytosis

    • In early endosomes, the LDL-receptor complex dissociates in mildly acidic environment

    • Receptors are recycled to the plasma membrane

    • LDL particles degraded in lysosomes (producing cholesterol, amino acids, fatty acids)

  • Pathway 2: Endocytosis of EGF and its Receptor

    • EGF binds its receptor, causing endocytosis

    • EGF-EGFR complexes remain stable in early endosomes; EGFR is inactivated by sequestration in intraluminal vesicles

  • Pathway 3: Endocytosis of Transferrin

    • Iron travels in blood as Fe(III) bound to transferrin

    • Two types of transferrin: apo-transferrin and holo-transferrin

    • Complex mechanisms involving clathrin-dependent endocytosis release Fe(III) in early endosomes where it's reduced to Fe(II) for cytoplasmic transport

  • Pathway 4: Transcytosis of Immunoglobulins

    • Involves transport from one side of a cell to another

    • Receptors (IgA and IgG) guide transport across epithelial/endothelial barriers

  • Exit from the Golgi Apparatus

    • The trans-Golgi network (TGN) serves as a sorting station

    • Main routes for exit: direct secretion to plasma membrane or transport to endosomes

    • Can be direct or indirect methods of transport

  • Secretory Pathway Mechanisms

    • Constitutive Secretion: Immediate fusion with the plasma membrane

    • Regulated Secretion: Occurs based on specific signals for hormones and enzymes

    • Various types of vesicles function differently in signaling and storage

  • Lysosomal Traffic and Hydrolases

    • Lysosomal enzymes tagged with mannose-6-phosphate (M6P) signal for recognition and transport

    • Disorders (like lysosomal storage diseases) can stem from defects in this process

  • Lysosomal Storage Diseases Overview

    • Large variety of diseases characterized by accumulation of materials in lysosomes leading to severe symptoms

    • Lysosomal storage disorders:

      • Defects in glycan degradation

      • Defects in lipid degradation

      • Defects in protein degradation

      • Defects in lysosomal transporters

      • Defects in lysosomal trafficking

  • Clinical and Genetic Implications

    • I-Cell disease (Inclusion-cell disease) leads to excessive accumulation in lysosomes, resulting in symptoms like skeletal anomalies and delayed development

    • Gaucher's Disease noted for specific genetic mutations and resultant clinical symptoms including hepatosplenomegaly and anemia

  • Key Structural Proteins

    • APs (Adaptor Proteins): Involved in the binding of clathrin and various cargo receptors, aiding transport and sorting

    • GGAs (Golgi-localized, gamma-adaptin ear-containing, Arf-binding proteins): Essential for processing lysosomal enzymes and some membrane proteins

  • Final Results from Endosomal Function

    • Receptors like mannose-6-phosphate and sortilin are crucial for transporting lysosomal enzymes back to/from the Golgi and their appropriate functional sites

    • Acidic environments of endosomes facilitate enzyme activity and receptor recycling to the Golgi.