Lecture 16: Programmed Cell Death - UMass Amherst€¦ · (Back in Lecture 7 notes) Programmed Cell...
Transcript of Lecture 16: Programmed Cell Death - UMass Amherst€¦ · (Back in Lecture 7 notes) Programmed Cell...
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Lecture 16: Programmed Cell Death
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Review Concepts of Apoptosis
When is apoptosis important?
Cell is damaged beyond repair
Cell is infected with a virus - can prevent viral spread
Removal of ineffective or potentially damaging immature B or T cells (remember back to T cell tolerance)
Control of malignant cells
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Two Distinct Apoptotic Pathways (Back in Lecture 7 notes)
Programmed Cell Death
Two distinct Pathways
Signaling & activation of Caspases
Intrinsic major pathway in all cells regulation of mito integrity release of key apoptotic factors Cytochrome C
Extrinsic death receptors (Fas) trimeric cell surface proteins bind to specific ligands (FasL) pro-apoptotic - mito leakage
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Apoptosis and Necrosis Paradigm
Typically cell death is discussed either as Apoptosis or Necrosis.
Apoptosis Active programmed process that is non-inflammatory Can be beneficial
Necrosis Passive, accidental cell death resulting from environmental perturbations with uncontrolled release of inflammatory cellular contents. Basically describing the end result of dead tissue. Almost always detrimental
In the end, only two terms to describe cell death is not sufficient.
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More Terms to Describe Dying Cells
Two Basic categories: Non-inflammatory Pro-inflammatory
6 Cell Death Pathways
Apoptosis Pyroptosis
Removal of unwanted and harmful cells
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New Pathway for Proinflammatory Cell Death
Apoptosis Word derivation - greek - falling off (such as leaves from a tree) Idea: controlled removal of individual components (cells) without destruction to organism. Pyroptosis
Word derivation - greek - roots "pyro," relating to fire or fever Idea: programmed cell death that results in inflammation (fire).
Pyroptosis Morphologicaly and mechanistically different from other cell death pathways Defining features: caspase-1 dependent
proinflammatory cytokines
8 New Pathway for Proinflammatory Cell Death
(recent! ~ 2001)
Caspase-1 is activated by cleavage - various stimuli Rapid formation of plasma membrane pores
Water influx osmotic swelling and lysis IL-1beta and IL-18 are processed and released
Nuclear integrity maintained
Possible mechanisms for cytokine release
Proinflammatory cytokine release
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Bacteria that Induce Pyroptosis
Cellular Exit
Shigella flexneri - T3SS factor IpaB Salmonella - T3SS factor flagellin
Rapid pyroptosis ~45 min
Terms: do not worry about the different inflammasome names
, SipB, IpaF
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Induces Apoptosis Mechanism
Cellular Exit
Sort of a centric view by these authors - they study Francisella!
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Mitochondrial Protein Import - Model Yeast
TOM translocase of
outer membrane
TIM translocase of
inner membrane
SAM sorting and assembly machinery
Import of proteins w/ N term targeting sequence Import of proteins w/ internal targeting sequence
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Import of Bacterial Factors into Mitochondria
Enteropathogenic E. coli EspF & Map T3SS factors:
N term targeting signals
Neisseria and Acinetobacter PorB & Omp38
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Bacterial Factors Targeting Host Mitochondria
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Back to Apoptosis Mechanism
Layers of Regulation via complex signaling events
1. Activation of caspase cascade FLIP - Flice-like inhibitory protein IAP - Inhibitor of apoptosis proteins
2. Anti-apoptotic proteins Bcl-2 like proteins
3. Expression of pro-survival factors NFκβ - transcription factor
4. Additional survival pathways AKT signaling pathway ERK signaling pathway
Pro-apoptotic
Pro-survival
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Bacteria Inhibit Apoptosis Three Main Ways
3 Main Inhibitory Routes
1. Interaction with caspases
2. Prevent cytochrome C release
3. Activation of survival pathways These also prevent cyt C release.
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16 Prevention of CytC
Release Cyt C:
A. Chlamydia proteasome-like activity factor CPAF: Targets BH3 proteins for degradation Outcome Bcl-2 proteins stabilized
B. Activation of AKT (phosphorylation) Prevents CytC release
C. Neisseria outer membrane protein PorB is target to mito
Inhibits CytC release
17 Prevention of CytC
Release Cyt C:
A. Chlamydia proteasome-like activity factor CPAF: Targets BH3 proteins for degradation Outcome Bcl-2 proteins stabilized
B. Activation of AKT (phosphorylation) Prevents CytC release
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Survival Pathways NFκβ: major pro-survival Transcription
factor - central role Exploit the cell survival pathways
A. Upregulation of pro-survival protein with accompanying downregulation of pro-apoptotic proteins
B. SopB - possibile activator of AKT Inhibits CytC release