Molecular and Biological Aspects of Apoptosis - Extrinsic pathway: role of death receptors
13 important questions on Molecular and Biological Aspects of Apoptosis - Extrinsic pathway: role of death receptors
What are the three types of death receptors?
- CD95/Fas receptor
- DR4 and DR5 receptors
- TNF receptor
Why is the CD95/Fas receptor essential for the removal of cells that threaten homeostasis?
- Autoreactive T cells with the potential to attack ''self'' are removed by apoptosis
- At the termination of an immune response when they are no longer needed
- Inflammatory cells in immune-privileged tissues (brain, eyes, testis)
- Inflammatory cells in a tumor
Other cells: virus infected cells
Multistep Fas activation
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Three types of cells killed by the Fas-FasL system
- Virus infected cells: cytotoxic T cells recognize MHC complex with viral antigen, inducing apoptosis via FasL.
- End of immune response: T-lymphocytes express both FasL and Fas. APC activates the receptors through MHC/antigen with T cell receptor.
- Removal of inflammatory cells: immune-privileged cells express FasL to kill cytotoxic T cell via Fas receptor.
Ways of Fas-mediated immune escape by tumors
- FasL-expressing tumors can induce T cell apoptosis.
- Cancer cells can be resistant to Fas-mediated apoptosis
- Cancer progression is associated with increased FasL expression
DR4, DR5 and its modulation by decoy receptors
Apoptosis signaling by DR4 and DR5 (TRIAL-R1/R2)
- Death Inducing Signaling Complex (DISC), which consists of FADD, RIP, pro-caspase-8
- Induction of apoptosis via caspase-8 directly to caspase-3, or by caspase-8 recruiting BID
- Mitochondrial signaling via Bax/Bak, releasing cytochrome C to form apoptosome with caspase-9 inducing caspase-3
- Inhibition of apoptosis by XIAP, which can inhibit caspase-3 and caspase-9
Tumor necrosis factor (TNF) signaling pathway
- TNFa ligands binds to receptor to activate it
- TRADD binds and activates kinase
- Kinase can activate NF-kB (transcription factor)
- If activated, it travels to the nucleus and transcribes inflammation factors and anti-apoptosis proteins.
Mechanism of NF-kB action
- Stimulation. Of TNFR1 leads to the binding of TRADD, recruiting FADD and TRAF2
- TRAF2 associates with RIP1 for IKK activation, which in turn phosphorylates the IkBa protein resulting in ubiquitination and dissociation from NF-kB
- NF-kB translocates to the nucleus where it binds to response elements in the DNA.
What does prolonged activation of TNF lead to?
RIP1 is part of which complexes?
- Complex I: activation of kinases, followed by activation of NF-kB
- Complex II: involved in apoptosis
- Necrosome: interaction with RIP3 to induce necrosis
How does RIPK3 induce necroptosis?
Role of ubiquitin in the TNF pathway
- RIP1 is polyubiquitinated by cIAPs, leading to the recruitment of TAK1 and IKK complexes
- IkBa is ubiquitinated, leading to NF-kB activation
- Deubiquitinated-RIP1 dissociates from TNF receptor forming complex II
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