Cell Quality Control
Peter Takizawa
Department of Cell Biology
Cellular quality control reduces production of
defective proteins.
Cells have many quality control systems to ensure that cell does not build up an excess amount of unfolded protein.
•Degradation of unfolded, cytosolic
proteins
•Unfolded protein response in the ER
•Autophagy
•Apoptosis
Cellular Control of Unfolded Proteins
Unfolded proteins aggregate via hydrophobic
interactions.
Proteins fold into three-dimensional structures with their hydrophobic domains buried within protein. Proteins that don’t fold properly have exposed
hydrophobic patches that can cause proteins to aggregate.
Several neurological diseases result from build up
of unfolded and misfolded protein.
Huntingtin
β-amyloid
The build up of aggregated protein can become cytotoxic to cells. Examples include Huntington’s and Alzheimer’s diseases where the accumulation of
aggregated protein in neurons leads to neurological defects.
Degradation machinery targets unfolded proteins
for digestion.
Chaperones
Chaperones
D
ig
es
tio
n
Cells have two ways to deal with unfolded proteins. Chaperones can bind to unfolded proteins to prevent them from aggregating and give them time to fold
properly. Alternatively, unfolded proteins can be digested.
Degradation machinery competes with chaperones
to bind unfolded proteins.
Folding
Competition between folding machinery (chaperones) and degradation machinery determines whether a protein is allowed more time to fold or is digested.
Chaperones and the degradation machinery both bind exposed hydrophobic patches in proteins because this is a sign that a protein is not folded. If
chaperones bind, the protein has more time to fold. If the degradation machinery binds, the protein is digested. Proteins that fold quickly and correctly are not
targeted for degradation. Proteins that take longer to fold are susceptible to degradation.
Degradation machinery competes with chaperones
to bind unfolded proteins.
Degradation
Competition between folding machinery (chaperones) and degradation machinery determines whether a protein is allowed more time to fold or is digested.
Chaperones and the degradation machinery both bind exposed hydrophobic patches in proteins because this is a sign that a protein is not folded. If
chaperones bind, the protein has more time to fold. If the degradation machinery binds, the protein is digested. Proteins that fold quickly and correctly are not
targeted for degradation. Proteins that take longer to fold are susceptible to degradation.
Chains of ubiquitin mark proteins for degradation.
Degradation
The mark that targets proteins for digestion is ubiquitin. Ubiquitin is peptide of 76 amino acids and is covalently attached to proteins on lysines. The presence
of ubiquitin on a protein can trigger different events and depends on the amount and arrangement of ubiquitin. For example, a single ubiquitin on histones
changes their arrangement on chromosomes. Multiple, single ubiquitin on receptor proteins triggers their inclusion in endocytic vesicles. A chain of ubiquitin
on a protein triggers digestion of that protein.
Chains of ubiquitin mark proteins for degradation.
Degradation
The mark that targets proteins for digestion is ubiquitin. Ubiquitin is peptide of 76 amino acids and is covalently attached to proteins on lysines. The presence
of ubiquitin on a protein can trigger different events and depends on the amount and arrangement of ubiquitin. For example, a single ubiquitin on histones
changes their arrangement on chromosomes. Multiple, single ubiquitin on receptor proteins triggers their inclusion in endocytic vesicles. A chain of ubiquitin
on a protein triggers digestion of that protein.
Chains of ubiquitin mark proteins for degradation.
Histone
regulation
Degradation
Endocytosis
The mark that targets proteins for digestion is ubiquitin. Ubiquitin is peptide of 76 amino acids and is covalently attached to proteins on lysines. The presence
of ubiquitin on a protein can trigger different events and depends on the amount and arrangement of ubiquitin. For example, a single ubiquitin on histones
changes their arrangement on chromosomes. Multiple, single ubiquitin on receptor proteins triggers their inclusion in endocytic vesicles. A chain of ubiquitin
on a protein triggers digestion of that protein.
Three enzymes mediate ubiquitylation of proteins.
The E1 enzymes uses ATP to transfer ubiquitin onto itself. The E1 then associates with E2/E3 and transfers ubiquitin to E2. The E3 targets E2 to correct
protein. There are 30 different E2s and hundreds of E3s allowing cells to target a variety of proteins.
E2 and E3 target specific proteins for
ubiquitylation.
Hydrophobic patch
E3 recognizes signal on target protein, for example an exposed hydrophobic patch. Once bound to the target and E2 transfers ubiquitin onto the target
protein. How a chain of ubiquitin is built is less clear. E1s could transfer more ubiquitin to E2 and E2 could add to the existing ubiquitin on the target protein.
Proteosome is a large complex of proteins that
digests ubiquitylated proteins.
The proteosome responsible for digesting most proteins and is highly abundant at 1% of total cell protein. The caps or the proteosome recognize signal on
protein that marks it for degradation (ubiquitin chains) and unfolds and feeds protein into core region. The core region contains enzymes that digests protein.
Proteosome contains several proteases that cleave
at specific sites in proteins.
acidic
basic
hydrophobic
The core contains several different types of proteases that cleave proteins after certain type of amino acids:
Beta2 cleaves after basic residues.
Beta1 cleaves after acidic residues.
Beta5 cleaves after hydrophobic residues.
These proteases allow the proteosome to digest almost any protein into small peptides.
Ubiquitylation and proteosome also mark and
digest folded proteins.
Stable
Ubiquitylated
and digested
Ubiquitin and proteosome are also used to digest folded proteins. Cell routine turnover of protein to maintain consistent concentration of protein. Cells also
turn off activity of certain proteins by degraded them. Most proteins contain a destruction domain that is recognized by E2/E3. The domain is hidden while the
protein is stable. Certain signals will exposes destruction domain leading to ubiquitylation and digestion.
Cells maintain specific concentrations of proteins
by balancing synthesis and protein degradation.
DNA
mRNA
Protein
Protein
Concentration
Ubiquitylation
Degradation
Protein concentration is maintained at stable level by balancing production and destruction of protein. Most proteins are synthesized at a certain rate and the
rate of destruction via ubiquitylation must match the production rate to hold concentration steady. Increases in protein concentration could arise via new
synthesis or by inhibiting destruction.
Recognizing and responding to unfolded
proteins in the ER.
The ER contains high concentration of unfolded protein and the accumulation of unfolded protein puts stress on ER. The ER has mechanisms to target
unfolded proteins for digestion. The ER also has mechanism to detect the amount of unfolded protein and increase the ability of ER to handle unfolded
protein.
Secretory cells are susceptible to accumulation of
unfolded protein in their ER.
Under normal conditions, secreted protein synthesized at basal rate. Often this rate is low enough so that proteins fold rather than aggregate. When
stimulated, some cells greatly increase protein production in the ER. This increases the concentration of unfolded protein in ER, making it more likely that
unfolded protein will aggregate rather than fold. B cells and insulin-secreting cells are susceptible to accumulation of unfolded protein in ER.
Secretory cells are susceptible to accumulation of
unfolded protein in their ER.
Under normal conditions, secreted protein synthesized at basal rate. Often this rate is low enough so that proteins fold rather than aggregate. When
stimulated, some cells greatly increase protein production in the ER. This increases the concentration of unfolded protein in ER, making it more likely that
unfolded protein will aggregate rather than fold. B cells and insulin-secreting cells are susceptible to accumulation of unfolded protein in ER.
Secretory cells are susceptible to accumulation of
unfolded protein in their ER.
Under normal conditions, secreted protein synthesized at basal rate. Often this rate is low enough so that proteins fold rather than aggregate. When
stimulated, some cells greatly increase protein production in the ER. This increases the concentration of unfolded protein in ER, making it more likely that
unfolded protein will aggregate rather than fold. B cells and insulin-secreting cells are susceptible to accumulation of unfolded protein in ER.
Secretory cells are susceptible to accumulation of
unfolded protein in their ER.
Under normal conditions, secreted protein synthesized at basal rate. Often this rate is low enough so that proteins fold rather than aggregate. When
stimulated, some cells greatly increase protein production in the ER. This increases the concentration of unfolded protein in ER, making it more likely that
unfolded protein will aggregate rather than fold. B cells and insulin-secreting cells are susceptible to accumulation of unfolded protein in ER.
Glycosylation pattern marks unfolded proteins in
the ER.
Glucose
Mannose
N-acetylglucosamine
Most proteins in ER receive sugars via N-linked glycosylation which adds a tree of 14 sugars. The glucose in the tree will serve as a marker to detect unfolded
proteins and target them to chaperones. The mannoses serve as a timer and targeting old, unfolded proteins for destruction.
Calnexin and glucosyl transferase prevent unfolded
proteins from leaving the ER.
Exit
Glu
e
as
sid
co
Glucosyl transferase
se
a
id
s
co
u
l
G
Calnexin
After synthesis and glycosylation, protein tries to fold. At the same time, glucosidase removes 2 glucoses from the sugar side chain. A side chain with a
single glucose is recognized by an ER proteins called calnexin. Calnexin keeps unfolded protein in the ER and recruits chaperones that help protein fold. When
glucosidase removes the final glucose, calnexin releases the protein. If the protein is folded, it leaves the ER. If not folded, glucosyl transferase binds the
exposed hydrophobic domains and adds glucose to sugar side chain. This allows the unfolded protein to rebind calnexin and try to fold again.
Mannosidase triggers degradation pathway for ER
proteins.
On top of the folding cycle, is the machinery that target proteins for degradation. The ER containsa low concentration of mannosidase. While protein is going
through folding cycle, there is a low probability that mannosidase will remove mannose residues. If mannose residues are trimmed, the protein is marked for
degradation. The mannoses function as timer for proteins: the longer a protein remains in ER, the more likely it will have mannose removed.
Mannosidase triggers degradation pathway for ER
proteins.
Degradation
On top of the folding cycle, is the machinery that target proteins for degradation. The ER containsa low concentration of mannosidase. While protein is going
through folding cycle, there is a low probability that mannosidase will remove mannose residues. If mannose residues are trimmed, the protein is marked for
degradation. The mannoses function as timer for proteins: the longer a protein remains in ER, the more likely it will have mannose removed.
EDEM and retrotranslocator export unfolded
proteins from lumen of ER.
EDEM
Cytosol
ER Lumen
EDEM( ER degradation-enhancing α-mannosidase-like protein) is protein in ER membrane that binds trimmed mannose. EDEM targets proteins to the
retrotranslocator which is a protein channel that spans ER membrane. In an energy-dependent process, unfolded protein is threaded through the
retrotranslocator into the cytosol. Chaperones in cytosol CDC48 needed to pull protein through channel.
Ubiquitin ligases on ER membrane tag
unfolded proteins with ubiquitin.
EDEM
Cytosol
ER Lumen
After exiting the ER, ubiquitin ligases on cytoplasmic side of ER membrane catalyze poly-ubiquitylation of protein.
Proteosome in cytosol degrades unfolded
ER proteins.
Cytosol
ER Lumen
Similar to unfolded cytosolic proteins, poly-ubiquitinated ER proteins are digested by the proteosome.
Responding to accumulation of unfolded
proteins in the ER
If the ER accumulates too many unfolded proteins, it creates ER stress. ER stress has recently been associated with several diseases, including diabetes,
Alzheimer’s, kidney disease and inflammatory bowel disease.
Three sensors detect amount of unfolded
protein in ER and generate response.
IRE1
PERK
ATF6
Chaperones
Lipid synthesis
Reduce translation
Chaperones
Lipid synthesis
Lumen
Cytosol
ER uses three different proteins to detect unfolded protein in ER: IRE1, PERK, ATF6. When activated by unfolded protein, the receptor elicit a cellular response
to alleviate the amount of unfolded protein. PERK reduces global translation by inactivating a key translation initiation factor. IRE1 and ATF6 turn on genes that
encode chaperones and lipid biosynthesis enzymes.
Unfolded protein removes chaperones from
IRE1, leading to dimerization and activation.
Lumen
One potential mechanisms by which IRE1 detects unfolded protein is through dimerization. IRE1 is only active as a dimer and chaperones in the ER lumen bind
IRE1 preventing dimerization. As the amount of unfolded protein rises in ER, the chaperone disassociates from IRE1 to bind the unfolded protein. IRE
dimerizes, leading to its activation.
Unfolded protein removes chaperones from
IRE1, leading to dimerization and activation.
Lumen
One potential mechanisms by which IRE1 detects unfolded protein is through dimerization. IRE1 is only active as a dimer and chaperones in the ER lumen bind
IRE1 preventing dimerization. As the amount of unfolded protein rises in ER, the chaperone disassociates from IRE1 to bind the unfolded protein. IRE
dimerizes, leading to its activation.
Unfolded protein removes chaperones from
IRE1, leading to dimerization and activation.
Lumen
One potential mechanisms by which IRE1 detects unfolded protein is through dimerization. IRE1 is only active as a dimer and chaperones in the ER lumen bind
IRE1 preventing dimerization. As the amount of unfolded protein rises in ER, the chaperone disassociates from IRE1 to bind the unfolded protein. IRE
dimerizes, leading to its activation.
Active IRE1 removes intron from RNA to
generate mRNA for transcription factor.
How does ER protein activate genes in nucleus? IRE1 contains nuclease activity that removes an intron from XBP1 RNA in cytosol, a tRNA ligase joins two exons
to produce XBP1 RNA that can be translated to produce a transcription factor. The transcription factor diffuses into nucleus and binds to upstream regulatory
elements in genes that encode chaperones and lipid biosynthesis enzymes.
Active IRE1 removes intron from RNA to
generate mRNA for transcription factor.
How does ER protein activate genes in nucleus? IRE1 contains nuclease activity that removes an intron from XBP1 RNA in cytosol, a tRNA ligase joins two exons
to produce XBP1 RNA that can be translated to produce a transcription factor. The transcription factor diffuses into nucleus and binds to upstream regulatory
elements in genes that encode chaperones and lipid biosynthesis enzymes.
Active IRE1 removes intron from RNA to
generate mRNA for transcription factor.
How does ER protein activate genes in nucleus? IRE1 contains nuclease activity that removes an intron from XBP1 RNA in cytosol, a tRNA ligase joins two exons
to produce XBP1 RNA that can be translated to produce a transcription factor. The transcription factor diffuses into nucleus and binds to upstream regulatory
elements in genes that encode chaperones and lipid biosynthesis enzymes.
Active IRE1 removes intron from RNA to
generate mRNA for transcription factor.
How does ER protein activate genes in nucleus? IRE1 contains nuclease activity that removes an intron from XBP1 RNA in cytosol, a tRNA ligase joins two exons
to produce XBP1 RNA that can be translated to produce a transcription factor. The transcription factor diffuses into nucleus and binds to upstream regulatory
elements in genes that encode chaperones and lipid biosynthesis enzymes.
Active IRE1 removes intron from RNA to
generate mRNA for transcription factor.
How does ER protein activate genes in nucleus? IRE1 contains nuclease activity that removes an intron from XBP1 RNA in cytosol, a tRNA ligase joins two exons
to produce XBP1 RNA that can be translated to produce a transcription factor. The transcription factor diffuses into nucleus and binds to upstream regulatory
elements in genes that encode chaperones and lipid biosynthesis enzymes.
Unfolded protein removes chaperone from
ATF, allowing it to move to Golgi.
ATF6 is kept in the ER through its association with chaperones. An increase in unfolded protein in the ER titrates BiP away from ATF6, allowing ATF6 to diffuse
into transport vesicles. When these vesicles fuse with the ER, proteases in the ER cleave the near the membrane-spanning domain of ATF6 to release the
cytoplasmic domain which is a transcription factor. The transcription factor diffuses into nucleus where it binds and activates that encode chaperones and
lipid biosynthesis enzymes.
Unfolded protein removes chaperone from
ATF, allowing it to move to Golgi.
ATF6 is kept in the ER through its association with chaperones. An increase in unfolded protein in the ER titrates BiP away from ATF6, allowing ATF6 to diffuse
into transport vesicles. When these vesicles fuse with the ER, proteases in the ER cleave the near the membrane-spanning domain of ATF6 to release the
cytoplasmic domain which is a transcription factor. The transcription factor diffuses into nucleus where it binds and activates that encode chaperones and
lipid biosynthesis enzymes.
Unfolded protein removes chaperone from
ATF, allowing it to move to Golgi.
ATF6 is kept in the ER through its association with chaperones. An increase in unfolded protein in the ER titrates BiP away from ATF6, allowing ATF6 to diffuse
into transport vesicles. When these vesicles fuse with the ER, proteases in the ER cleave the near the membrane-spanning domain of ATF6 to release the
cytoplasmic domain which is a transcription factor. The transcription factor diffuses into nucleus where it binds and activates that encode chaperones and
lipid biosynthesis enzymes.
Unfolded protein removes chaperone from
ATF, allowing it to move to Golgi.
ATF6 is kept in the ER through its association with chaperones. An increase in unfolded protein in the ER titrates BiP away from ATF6, allowing ATF6 to diffuse
into transport vesicles. When these vesicles fuse with the ER, proteases in the ER cleave the near the membrane-spanning domain of ATF6 to release the
cytoplasmic domain which is a transcription factor. The transcription factor diffuses into nucleus where it binds and activates that encode chaperones and
lipid biosynthesis enzymes.
Unfolded protein removes chaperone from
ATF, allowing it to move to Golgi.
e
s
a
e
t
o
Pr
ATF6 is kept in the ER through its association with chaperones. An increase in unfolded protein in the ER titrates BiP away from ATF6, allowing ATF6 to diffuse
into transport vesicles. When these vesicles fuse with the ER, proteases in the ER cleave the near the membrane-spanning domain of ATF6 to release the
cytoplasmic domain which is a transcription factor. The transcription factor diffuses into nucleus where it binds and activates that encode chaperones and
lipid biosynthesis enzymes.
Unfolded protein removes chaperone from
ATF, allowing it to move to Golgi.
e
s
a
e
t
o
Pr
ATF6 is kept in the ER through its association with chaperones. An increase in unfolded protein in the ER titrates BiP away from ATF6, allowing ATF6 to diffuse
into transport vesicles. When these vesicles fuse with the ER, proteases in the ER cleave the near the membrane-spanning domain of ATF6 to release the
cytoplasmic domain which is a transcription factor. The transcription factor diffuses into nucleus where it binds and activates that encode chaperones and
lipid biosynthesis enzymes.
Unfolded protein removes chaperone from
ATF, allowing it to move to Golgi.
e
s
a
e
t
o
Pr
ATF6 is kept in the ER through its association with chaperones. An increase in unfolded protein in the ER titrates BiP away from ATF6, allowing ATF6 to diffuse
into transport vesicles. When these vesicles fuse with the ER, proteases in the ER cleave the near the membrane-spanning domain of ATF6 to release the
cytoplasmic domain which is a transcription factor. The transcription factor diffuses into nucleus where it binds and activates that encode chaperones and
lipid biosynthesis enzymes.
Prolonged activation of PERK and ATF6 trigger the
apoptosis pathway.
IRE1
PERK
ATF6
Lumen
Cytosol
Chaperones
Chaperones
Lipid synthesis
Reduce
Translation
Apoptosis
When unfolded proteins start to accumulate in the ER, cells respond through the activation of the different receptors and their downstream effectors. However,
if these responses are insufficient and the amount of unfolded protein remains high, the receptors will trigger an alternative pathway that leads to cell death
via apoptosis. Common response of cells to interior and exterior changes. Cells try to adapt to changes by altering pathways or turning on certain pathways. If
these don’t allow the cell to adapt to the new conditions, cell will undergo cell death.
Autophagy mediates digestion of proteins,
organelles and intracellular pathogens.
Lysosome
Autophagy or self-eating is the process in which the cell encloses a portion of its cytoplasm in a membrane-bound structure or autophagosome.
Autophagosomes fuse with the lysosome where enzymes in the lysosome degrade the cytoplasmic macromolecules and organelles into smaller subunits (i.e.
amino acids, nucleotides, sugars). These can be reused to make new macromolecules or catabolyzed to generate energy. Autophagy was originally thought to
be used only to generate energy when cells can generate enough ATP by normal mechanisms (i.e. during starvation). More recently, autophagy has been found
to be a way for cells to get rid of old or damaged organelles and protein aggregates in the cytoplasm. In addition, autophagy is also used to destroy
intracellular pathogens such as listeria.
Apoptosis: Orderly removal of malfunctioning cells
Apoptosis is ordered cell death that avoids
damage to surrounding cells and tissue.
Necrotic Cell
Apoptotic Cell
It’s important to contrast necrosis with apoptosis. Necrosis results when cells undergo traumatic injury, mechanical, electrical or heat. Irreversibly damages
the cell, usually the plasma membrane. Complete loss of cytoplasmic material that spreads to surrounding cells and tissues. Releases harmful cellular
components and triggers inflammation.
Apoptosis is ordered cell death where organelles breakdown and cellular structure are digested. Importantly, the plasma membrane remains intact in
apoptotic cells preventing the release of cellular material to surrounding cells. Apoptotic cells are recognized by cells of the immune system, in particular
Apoptosis is ordered cell death that avoids
damage to surrounding cells and tissue.
Necrotic Cell
Apoptotic Cell
Macrophage
It’s important to contrast necrosis with apoptosis. Necrosis results when cells undergo traumatic injury, mechanical, electrical or heat. Irreversibly damages
the cell, usually the plasma membrane. Complete loss of cytoplasmic material that spreads to surrounding cells and tissues. Releases harmful cellular
components and triggers inflammation.
Apoptosis is ordered cell death where organelles breakdown and cellular structure are digested. Importantly, the plasma membrane remains intact in
apoptotic cells preventing the release of cellular material to surrounding cells. Apoptotic cells are recognized by cells of the immune system, in particular
Apoptosis can be triggered by external and internal
signals.
Apoptosis
Apoptosis can be triggered from both external cues or internal cues. Extrinsic cues usually come from other cells that bind to the target cell via specific
receptors. Once bound, these receptors trigger apoptosis in the target cell. External apoptosis is one way that the immune system kills virus-infected cells.
Intrinsic apoptosis involves internal signals that trigger apoptosis. Interestingly, the trigger for apoptosis appears to come from mitochondria. A signal to
initiate apoptosis, causes certain proteins in the membrane of mitochondria to cluster and form channel. This channels allows small proteins and other
components to leak into the cytosol of cell. Some of these small proteins initiate apoptosis.
Apoptosis can be triggered by external and internal
signals.
PERK
ATF6
Apoptosis
Apoptosis can be triggered from both external cues or internal cues. Extrinsic cues usually come from other cells that bind to the target cell via specific
receptors. Once bound, these receptors trigger apoptosis in the target cell. External apoptosis is one way that the immune system kills virus-infected cells.
Intrinsic apoptosis involves internal signals that trigger apoptosis. Interestingly, the trigger for apoptosis appears to come from mitochondria. A signal to
initiate apoptosis, causes certain proteins in the membrane of mitochondria to cluster and form channel. This channels allows small proteins and other
components to leak into the cytosol of cell. Some of these small proteins initiate apoptosis.
Apoptosis initiated by activation of proteases
through caspase cascade.
Inactive
caspase
Active
caspase
Apoptosis
Signal
Both external and intrinsic apoptosis cause cell death by the cell process: activation of caspases. Caspases are proteases that are kept in an inactive state in
healthy cells. When a cell receives and apoptotic signal, certain type of caspases is activated. This caspase can activate several other downstream caspases.
Each of the initial caspases is capable of activating several downstream caspases, amplifying the signal in what is called the caspase cascade. The downstream
caspases are also proteases that are capable of digesting cellular proteins to cause cell death.
Apoptosis initiated by activation of proteases
through caspase cascade.
Both external and intrinsic apoptosis cause cell death by the cell process: activation of caspases. Caspases are proteases that are kept in an inactive state in
healthy cells. When a cell receives and apoptotic signal, certain type of caspases is activated. This caspase can activate several other downstream caspases.
Each of the initial caspases is capable of activating several downstream caspases, amplifying the signal in what is called the caspase cascade. The downstream
caspases are also proteases that are capable of digesting cellular proteins to cause cell death.
Apoptosis initiated by activation of proteases
through caspase cascade.
Both external and intrinsic apoptosis cause cell death by the cell process: activation of caspases. Caspases are proteases that are kept in an inactive state in
healthy cells. When a cell receives and apoptotic signal, certain type of caspases is activated. This caspase can activate several other downstream caspases.
Each of the initial caspases is capable of activating several downstream caspases, amplifying the signal in what is called the caspase cascade. The downstream
caspases are also proteases that are capable of digesting cellular proteins to cause cell death.
Apoptosis initiated by activation of proteases
through caspase cascade.
Both external and intrinsic apoptosis cause cell death by the cell process: activation of caspases. Caspases are proteases that are kept in an inactive state in
healthy cells. When a cell receives and apoptotic signal, certain type of caspases is activated. This caspase can activate several other downstream caspases.
Each of the initial caspases is capable of activating several downstream caspases, amplifying the signal in what is called the caspase cascade. The downstream
caspases are also proteases that are capable of digesting cellular proteins to cause cell death.
Apoptosis initiated by activation of proteases
through caspase cascade.
Both external and intrinsic apoptosis cause cell death by the cell process: activation of caspases. Caspases are proteases that are kept in an inactive state in
healthy cells. When a cell receives and apoptotic signal, certain type of caspases is activated. This caspase can activate several other downstream caspases.
Each of the initial caspases is capable of activating several downstream caspases, amplifying the signal in what is called the caspase cascade. The downstream
caspases are also proteases that are capable of digesting cellular proteins to cause cell death.
Take home points...
• Unfolded proteins in the cytosol are tagged by ubiquitin and degraded by
proteosome.
• Excess unfolded protein in the ER triggers the unfolded protein response.
• Autophagy allows cells to degrade large protein aggregates, organelles and
intracellular pathogens.
• Apoptosis is an ordered progression of cell death that avoids triggering
inflammation.