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

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

2. 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.

3. 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.

4. Eg: When autophagy is compromised genetically or pharmacologically（药理学的）, 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.

5. autophagy itself is a ‘pro-death’ process or results in cell death by regulating apoptosis During Drosophila(果蝇）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

6. 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( 足叶乙甙） ,（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.

7. Whether autophagy functions in cell survival or cell death may depend on the level of autophagy induced during a given physiological condition.

8. Autophagy as an antimicrobial defence mechanism

9. autophagy plays an important role in the elimination of intracellular and extracellular pathogens. Eg:the plant virus TMV accumulated to a higher level in Beclin 1-silenced plants than in wild-type plants

10. 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.

11. 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(雷帕霉素） actively inhibits the survival of the facultative intracellular pathogen Mycobacterium tuberculosis（肺结核分支杆菌） Similarly, autophagic vesicles effectively engulf and destroy invading extracellular pathogens such as group A Streptococcus（链球菌） (GAS). （Autophagy-deficient atg5-/- mutant ES cells are incapable of eliminating GAS, allowing it to survive and Proliferate.）

12. 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.

13. 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