apoptotic triggers include
- DNA damage that can’t be repaired in a timely manner
- no growth factors
- low nutrients/starvation
- cytotoxic T-cell kills a sick cell
- EX: virally-infected cells
huge structural changes occur within dying cells
how do huge structural changes occur within dying cells
activation of a small family of proteases: Caspases
initiator caspases
become active in response to a signal
some way to detect that the cell is damaged or infected
- activation by induced proximity:
- something gets initiators to dimerize
- they then cleave each other to form an active enzyme
Initiator caspases activate…
executioner caspases
- ~1,000 different proteins are cleaved by executioner caspases during apoptosis
- destroying these proteins (or a subset of them) destroyes the cell and breaks it into parts
active executioner caspase cleaves a DNase Inhibitor (iCAD)
besides the DNA, caspases destroy:
- nuclear lamins, cell-cell or cell-matrix adhesions, cytoskeleton
- allows cells to disconnect from neighbors, round up and break up into pieces
what triggers initiation of initiator caspases?
two types: caspase 8 (extrinsic pathway) and caspase 9 (intrinsic pathway)
initiator caspase 8 activation
signal comes from cell-cell contact
DISC
initiator caspase 8 activation: death-inducing signaling complex (DISC) forms
initiator caspases: caspase 9
intrinsic pathway: caspase 9
intrinsic pathway begins with:
loss of mitochondrial outer membrane integrity
intrinsic pathway
inner mitochondrial membrane
intrinsic pathway begins with loss of mitochondrial outer membrane integrity
inner mitochondrial membrane: electron transport to drive ATP synthesis
cytochrome c in intrinsic pathway beginning
intrinsic pathway begins with loss of mitochondrial outer membrane integrity
- cytochrome c does more than electron transport
- releasing cytochrome c (among others) into the cytosol
example: cytochrome c release into cytosol(and nucleus, because it’s small)
cytochrome c binds…
adaptor protein Apaf1 (apoptotic protease activating factor)
adaptors form oligomer: forms apoptosome
Apaf1
apoptotic protease activating factor
why does outer mitochondrial membrane lose integrity? And how do cells control when this happens?
Bcl2 family
Bcl2 family breakdown
Effector Pro-Apoptotic Bcl2 family
Bax or Bak form pores in mitochondrial outer membrane
Anti-apoptotic Bcl2 family
- prevent pore formation by Bak or Bax
- At least 5 anti-apoptotic Bcl2 family proteins in our cells.
- need at least 1 for cell survival
- Inhibit pore formation and/or bind Bax in cytosol and prevent it from binding the mitochondrial outer membrane
- Must be inhibited to get apoptosis initiated (must inhibit the inhibitor)
BH3-only Pro-Apoptotic Bcl2 family
- inactivate the anti-apoptotic Bcl2 proteins
- The BH3-only proteins are the critical link between detection of signals that something is wrong and activation of the intrinsic pathway of apoptosis
EXAMPLE: cell survival signals block BH3-only proteins from activating apoptosis
- our cells need survival signals
- without these, they will activate apoptosis
- one example of how a survival factor prevents apoptosis
- Bcl2 is anti-apoptotic and Bad is BH3-only pro-apoptotic
