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Summary Biogenesis of lysosomes
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Voortgezette Celbiologie Evelien FloorBiogenesis of lysosomes
Introduction in lysosome biogenesis
Lysosomes are intracellular organelles filled with hydrolytic enzymes and surrounded by a single
membrane. They are the key compartments in the cell for degradation and recycling of biomolecules.
Lysosomes are NOT passive garbage collectors, but actively control energy metabolism and cellular
homeostasis. Dysfunctional lysosomes are associated with a variety of human disorders, ranging
from rare metabolic diseases to Alzheimer and cancer.
Pathways to the lysosome:
Endocytosis; uptake of extracellular
material
Autophagy; digestion of intracellular
molecules
Biosynthesis; input of newly
synthesized lysosomal proteins
Endocytosis
Endocytosis is the uptake of biomaterials via
insertion of parts of the plasma membrane.
It is the main entrance into the cell.
Molecules that enter the cells via
endocytosis:
1. Essential molecules: nutrients,
hormones, growth factors
2. Pathogens: viruses, bacteria
3. Drugs, medicines
A different kind of endocytosis is phagocytosis or pinocytosis. Phagocytosis is for bigger particles, and
pinocytosis is for fluid uptake. Clathrin mediated endocytosis is for receptors.
The first step in endocytosis is vesicle formation from the plasma membrane. Those vesicles travel to
the early endosome. The vesicles are taken up by the early endosome and inside the early endosome
there are called intraluminal vesicles (ILV). Eventually the early endosome will form a late endosome.
The early endosomes are very important decision makers in the cell because they chose whether ILV
are imported or recycled.
The epidermal growth factor receptor (EGFR) enters the cell
via clathrin mediated endocytosis and moves to the early
endosome. The vesicles can be inserted to form ILV or they
can be recycled. The endosomal sorting complex required
for transport (ESCRT) recognizes ubiquitinated EGFR and
drives the inward move. ESCRT is specific for
transmembrane proteins that are ubiquinated. Once the
EGFR enters an ILV it can’t be recycled anymore. In this way
ESCRT makes sure that EGFR won’t be recycled the whole
time.
The transferrin receptor (TfR) is necessary for import of
ferritin (iron) into the cell. Those receptors bind to ferritin
and are endocytosed. In the early endosome there is a
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slightly lower pH what results in the release of the ferritin. Afterwards, the TfR can be recycled or
move to the lysosome for degradation.
Late endosomes and lysosomes can fuse with the plasma membrane for waste disposal, secretion of
lysosomal enzymes, secretion of exosomes and plasma membrane repair. However, they also release
digested content into the cytosol for de novo synthesis of proteins and lipids.
Lysosomes can sense nutrient status and signal this to the nucleus. Therefore, they are not passive
but active organelles. mTOR can phosphorylate TFEB which is a transcription factor that remains in
the cytosol when it is phosphorylated. In case of starvation mTOR is released from the lysosome and
TFEB will no longer be phosphorylated. TFEB then moves to the nucleus where it induces the
expression of lysosomal-autophagic genes. Autophagy and endocytosis will then cause an increase in
nutrients.
Autophagy
Autophagy is self-eating or cannibalism: use of cellular components to generate energy or new
molecular building blocks. Autophagy is a basic mechanism that always happens in the cell. Cancer
cells use autophagy for energy metabolism.
In case of starvation or hypoxia, cells are starting to use intracellular components for energy. The first
stage of autophagy is formation of a membrane which starts to grow and isolate molecule from the
cytoplasm (non-selective autophagy). The second stage is selective autophagy, the isolation
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