Virus + apoptosis Flashcards
Some molecular mechanisms of apoptosis?
Fas ligand + Fas –> Death domain proteins –> Caspases –> CELL DEATH
TNF –> TNFR –> Death domain proteins –> Caspases –> CELL DEATH
ER Stress –> Cytochrome C release in mitochondria –> Caspases –> CELL DEATH
p53 –> Bcl family –> Cytochrome C release in mitochondria –> Caspases –> CELL DEATH
How does p53 intrinsic induce apoptosis?
Normally it is ubiquitinated by Mdm2 ubiquitin ligase = causes p53 to degrade
If cells are subjected to stress (ie. hypoxia, low rNTPs) they become phophoylated = stable protein
What is pRb and when does is it affected in the cell cycle?
pRb = phosphorylated tumour supressor protein
Increasingly phosphorylated during progression through G1 and is maintained in a hyperphosphorylated state until late mitosis
Rb physically associates with E2F factors and blocks their ability to activate expression of genes that encode products necessary for S-phase progression
After S-phase, E2F released + binds to promoters
EF2 is rejoined to Rb after mitosis
How does p53 + pRb cordinate to make sure everything is ok?
If E2F is unbound to Rb, E2F is left to replicate DNA which can cause tumours.
Once Rb is detached from E2F, it loses of Rb function
and it phosphorylates p53 which suppresses tumour formation in DNA replication
Examples of oncogenic viruses that target both p53 and pRb?
Adenovirus, SV40, HCV + HBV
Role of mitochondria in apoptosis?
Mitochondrial permeability transition pore:
> CLOSED:
By Bcl-2 family –> Anti-apoptotic
> OPENED:
By Bax –> Pro-apoptotic
Loss of mitochondrial membrane potential and Cytochrome C release:
Cytochrome C + Apaf-1 + dATP = Apoptosome of Procaspase-9 –> Caspase-9 = CELL DEATH!!
How do viruses inhibit mitochondrial apoptosis pathway?
Virus creates Bcl-2 homologues - Bcl-2 family closes Mitochondrial permeability transition pore = Anti-apoptotic
This inhibit loss of ΔΨm and cytochrome C release so no apoptosome are produced
How ER stress leads to apoptosis?
ER stress = Accumulation of unfolded proteins
Accumulation of unfolded proteins can trigger Unfolded Protein Response, which tries to respond by:
- Reduction in protein translation
- Induction of ER chaperone expression
If still unsuccessful, Ca2+ release activates Caspase 12 ==> CELL DEATH!!!
What is the Unfolded Protein Response?
Response by BiP detects unfolded protein – chaperone
- Unfolded proteins accumulate into the ER BiP dissociates from it’s molecule (Ire1, etc) binds to unfolded protein
- Ire1 once displaced splices mRNA to make a truncated form.
- The protein produced from truncated mRNA - active transcription factor to XBP-1
- ATF6 once displaced by BiP is cleaved and attaches onto the same protein
- PERK phosphorylates Eif-2a - stops translation
How does Fas/TNFR induce apoptosis?
Fas ligand & Fas complex + TNF & TNFR interact with death domain, causes Caspase 8 to convert Procaspase 3 –> Caspase 3 = CELL DEATH!!!
TNFR activates cPLA2 which cleaves lipids + arachidonic acid = CELL DEATH!!!
How does Adenovirus E3 region expresses inhibitors for apoptosis?
- RID causes death domain proteins to undergo lysosome
- 14.7K inhibits Caspase 3 = NO CELL DEATH!!!
- RID + 14.7K inhibits cPLA2 = NO CELL DEATH!!!
How do large DNA viruses inhibit apoptosis?
> vFLIP’s - viral FLICE-like Inhibitory Proteins
Interact with FADD (death domain) and prevent recruitment and activation of caspases
Hallmark of apoptosis?
Exposure of the plasma membrane lipid phosphatidylserine (PS) on the cell surface
In infected cells - Flippase enzyme is cleavage – PS is exposed to out membrane – signals to others cells it is undergoing apoptosis
PS is then recognised by specific direct/in-direct receptors on phagocytes (and other cells)
