EndoCytosis and Lysosomal System Exam Review

Gaucher disease

A lysosomal storage disease caused by a defect in the enzyme beta-glucocerebrosidase

Oral/craniofacial presentation of Gaucher disease (case example)

Bilateral mandibular lesions were reported in a 30-year-old male with Gaucher disease (Zeevi et al., J. Oral Maxillofac. Surg 2013)

Gaucher cell

An abnormal, lipid-laden macrophage that accumulates in Gaucher disease due to failure to break down glucocerebroside

Treatment example for Gaucher disease

Enzyme replacement therapy (illustrated by a 37-year-old female with a single mandibular lesion)

Pinocytosis

"Cell drinking" — a form of endocytosis involving small vesicles less than 150 nm that occurs indiscriminately

Macropinocytosis

A form of endocytosis producing larger vesicles than pinocytosis; also indiscriminate (not receptor-specific)

Clathrin-associated receptor-mediated endocytosis

A form of endocytosis using vesicles about 100-150 nm in size that relies on specific receptors for specific cargo

Caveolae

"Little caves" — small endocytic invaginations about 50-80 nm in size that are especially important in endothelial cells

Phagocytosis

"Cell eating" — a form of endocytosis involving large vesicles up to 10 micrometers, used to engulf microorganisms and cell debris

What distinguishes receptor-mediated endocytosis from simple pinocytosis?

Receptor-mediated endocytosis achieves roughly a 1000-fold concentration of specific cargo compared with simple (indiscriminate) pinocytosis

Examples of cargo taken up via clathrin-associated receptor-mediated endocytosis

Cholesterol, vitamin B12, iron, and viruses such as Influenza A and SARS-CoV-2

How much plasma membrane do macrophages endocytose, and how quickly?

Macrophages can endocytose the equivalent of 100% of their plasma membrane every 30 minutes

How is plasma membrane area maintained despite continuous endocytosis?

It is balanced — as much membrane is added back to the cell surface by exocytosis as is removed by endocytosis

Clathrin

A coat protein that assembles on the cytoplasmic face of the plasma membrane to form clathrin-coated pits, which pinch off into clathrin-coated vesicles during receptor-mediated endocytosis

Clathrin-coated pit

An invagination of the plasma membrane coated with clathrin protein that captures receptor-bound cargo before budding off as a vesicle

Fate of clathrin-coated vesicles after budding

The clathrin coat is shed shortly after budding, and the uncoated vesicle can then fuse with an endosome

Receptor recycling (clathrin pathway)

After cargo is released, many receptors are recycled back to the plasma membrane via vesicles rather than being degraded

LDL receptor and PCSK9

PCSK9 binding to the LDL receptor reroutes it toward lysosomal degradation instead of recycling back to the plasma membrane, reducing LDL receptor availability and raising plasma LDL levels

Why are PCSK9 inhibitor antibodies used clinically?

They block PCSK9 from rerouting and degrading LDL receptors, allowing more LDL receptors to recycle to the surface and lowering plasma LDL cholesterol

Early endosome

The first sorting compartment cargo reaches after endocytosis, where receptor-ligand dissociation and sorting decisions (recycling vs. degradation) begin

Maturation pathway from endosome to lysosome

Endosome → multivesicular body → late endosome → lysosome

Multivesicular body

An intermediate endosomal compartment containing small internal vesicles, formed during endosome maturation toward the lysosome

Late endosome

A more acidic, mature endosomal compartment that forms after the multivesicular body and precedes fusion with/maturation into a lysosome

How can cargo/receptor dissociation inside endosomes be triggered?

By the acidic pH of the endosome, which can cause ligand-receptor complexes to dissociate

Fate of EGF and its receptor after internalization

Unlike many recycled receptors, internalized EGF and the EGF receptor are typically routed for degradation in the lysosome

Lysosome

A membrane-bound organelle containing acid hydrolases that degrades macromolecules, damaged organelles, and internalized material

Lysosomal enzymes (acid hydrolases)

Enzymes with an optimal pH of about 5.0 or lower, including proteases, nucleases (DNase and RNase), glycosidases, sulfatases, lipases, phospholipases, and phosphatases

Why do lysosomal enzymes require an acidic pH?

Because they are acid hydrolases that function optimally at pH ≤ 5.0, which also helps protect the rest of the cell if they leak out, since cytosolic pH is neutral

Mannose-6-phosphate (M6P)

A modification added to lysosomal enzymes in the Golgi that serves as a tag directing them to the lysosome via M6P receptors

Autophagy

A cellular process in which components of the cytoplasm, including organelles, are engulfed by a double membrane and delivered to lysosomes for degradation

Autophagosome

A double-membraned vesicle that forms around cytoplasmic material (such as damaged mitochondria) during autophagy before fusing with a lysosome

What triggers increased autophagosome activation?

Cell starvation triggers increased autophagosome formation and activity

What can autophagosomes selectively engulf?

Damaged or unwanted organelles, such as mitochondria, in addition to bulk cytoplasmic contents