Endocytosis 2

Major Endocytic Compartments

  • Endocytic vesicles

  • Early endosomes

  • Recycling endosomes

  • Late endosomes / multivesicular bodies

  • Lysosomes

Pathways of Endocytosed Cargo

Overview

  • Exit from the Golgi to the cell surface

  • Trafficking from the Golgi apparatus to endosomes

Pathways

  • Pathway 1: LDL

    • Implications: Atherosclerosis, heart attacks, stroke

    • Process:

    • LDL binds receptor on plasma membrane.

    • Internalized via clathrin-dependent endocytosis.

    • Complex dissociates in early endosomes; receptor recycled, LDL degraded in lysosome.

  • Pathway 2: EGF and EGFR

    • Significance: Growth factor, cancer

    • Process:

    • EGF binds EGFR, inducing endocytosis.

    • Complex is stable in early endosomes; EGFR inactivated via sequestration in intraluminal vesicles.

  • Pathway 3: Iron (Transferrin)

    • Details:

    • Two transferrin forms: apo-transferrin (empty) and holo-transferrin (bound to Fe).

    • Internalization occurs via clathrin-dependent endocytosis; Fe(III) released in early endosomes and reduced to Fe(II) before entering cytoplasm.

    • Apo-transferrin-receptor complex recycled back to membrane.

  • Pathway 4: Transcytosis (Immunoglobulin)

    • Function: Transport of cargo across epithelial/endothelial cells

    • Mechanism involves receptors for immunoglobulin transcytosis.

  • Pathway 5: Endothelial Transcytosis (Albumin, Cavolae)

    • Mechanisms similar to transcytosis of immunoglobulins covered above.

  • Pathway 6: Phagocytosis

    • Details to be discussed next week.

Golgi Apparatus and Secretion

  • Export Mechanism:

    • Two main routes: secretion to plasma membrane, cargo transport to endosomes.

    • Transport can be direct or indirect via carriers.

  • Secretion Types:

    • Constitutive Secretion: All cells, immediate fusion with plasma membrane.

    • Regulated Secretion: Involves hormones, neurotransmitters, and requires signals.

Endocytic Pathways and Protein Targeting

  • Polarity in Epithelial Cells:

    • Tight junctions prevent lateral migration of TM proteins.

    • Proteins are sorted based on signals recognized at TGN (Trans-Golgi Network).

  • Basolateral Sorting Signals:

    • Tyrosine-based or dileucine motifs involved in recruitment to clathrin-coated vesicles.

Lysosomal Targeting

  • Enzymes and Membrane Proteins:

    • Targeted based on dileucine and tyrosine motifs interacting with respective adaptors (GGA or AP-3).

  • Lysosomal Storage Diseases:

    • Categories: Defects in glycan, lipid, protein degradation; defects in transporters and trafficking.

    • Classical presentations include neurodegeneration, particularly in infancy/childhood.

  • I-Cell Disease:

    • Most severe lysosomal storage disease caused by a defect in trafficking hydrolases; symptoms include developmental delay and coarse facial features.

Summary of Mechanisms

  • Clathrin Coats and Adaptors:

    • Human cells use clathrin/AP-1 and AP-3 complexes for lysosomal protein targeting.

  • Retromer Function:

    • Involved in the retrieval of cargo from late endosomes back to the Golgi, ensuring proper lysosomal enzyme processing.

  • Final Conclusion:

    • Successful transport pathways are essential for cellular function, highlighting the complexity of endocytic/recycling pathways and their impact on health.