Autophagy and viability: pro-survival or pro-death?

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Autophagy and viability
pro-survival or pro-death?
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Compounding the intrigue was the discovery that
Beclin 1 interacts with Bcl-2, suggesting
surprising novel crosstalk between two potential
cell death pathways.
Two opposing hypotheses have emerged autophagy
assists in the death of cells or autophagy
protects the cell from death. Recent evidence
suggests that both hypotheses may be correct
depending on the cell type, stimuli and
developmental stage.
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autophagy plays a crucial role in cell survival
during PCD
autophagy promotes cell survival during nutrient
starvation by degrading and recycling nutrients.
Autophagy may also indirectly promote cell
survival by retarding or preventing apoptosis.
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Eg When autophagy is compromised genetically or
pharmacologically(????), HeLa cells die via an
apoptotic pathway. This death is abolished
using Bcl-2 or caspase inhibitors suggesting that
autophagy prolongs survival by deterring the
onset of apoptosis.
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autophagy itself is a pro-death process or
results in cell death by regulating apoptosis
During Drosophila(??)development, autophagy is
essential to activate the PCD required to
eliminate unwanted salivary glands. Consistent
with this concept, several Drosophila ATG genes
are upregulated in dying salivary glands
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in the absence of apoptosis, autophagy can
actively contribute to execution of cell death.
Overexpression of Bcl-2 or Bcl-XL(Autophagy
mediated death seems to depend on Bcl-XL) in
wild-type mouse embryonic fibroblasts treated
with etoposide( ????) ,(a common apoptotic
reagent), resulted in increased autophagosome
Formation, because an increase in autophagosome
formation was correlated with cell death.
The non-apoptotic death was dependent on
functional autophagic mechanisms. because
silencing of ATG5/beclin 1 abolished death when
treated with etoposide.
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Whether autophagy functions in cell survival or
cell death may depend on the level of autophagy
induced during a given physiological condition.
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Autophagy as an antimicrobial defence
mechanism
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autophagy plays an important role in the
elimination of intracellular and extracellular
pathogens.

Egthe plant virus TMV accumulated to a higher
level in Beclin 1-silenced plants than in
wild-type plants
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These results indicate that autophagy functions
as an antiviral defence mechanism. The increase
in virus accumulation in autophagy deficient
cells suggests that ATG proteins might target
cellular factors or pathways required for virus
replication and spread.
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In animals, recent findings indicate that
autophagy is also used to combat against
bacterial pathogens.
Autophagy induced by nutrient starvation or by
treatment with rapamycin(????) actively inhibits
the survival of the facultative intracellular
pathogen Mycobacterium tuberculosis(???????)
Similarly, autophagic vesicles effectively
engulf and destroy invading extracellular
pathogens such as group A Streptococcus(???)
(GAS). (Autophagy-deficient atg5-/- mutant ES
cells are incapable of eliminating GAS, allowing
it to survive and Proliferate.)
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It seems some bacteria have evolved effective
counter-defence strategies to subvert autophagy
and promote successful infection.
1?Some bacterial and viral pathogens have
evolved to utilize the autophagy machinery for
replication or survival inside the host cell
Autophagosomal-like vesicles provide a
replicative niche for a (variety of pathogens
including Legionella pneumophila, and Bru- ella
abortus .) 2?While hiding inside
autophagosomes, these pathogens eplicate and
either restricts autophagosome maturation or
delay fusion with the lysosome.
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3?The invasive pathogen Porphyromonas gingivalis
even stimulates autophagosome formation and uses
them to enter the host cells. 4?Similarly,
poliovirus and mouse hepatitis virus (MHV) induce
the formation of autophagosome-like
double-membrane vesicles (DMV) and use them as a
replicative niche. eg In atg5-/-ES cells
infected with MHV, formation of DMV is inhibited
and replication of the virus is drastically
reduced indicating that autophagy is required for
efficient replication of MHV