Molecular Mechanisms involved in autophagy: Role in microorganism survival.

COLOMBO, M. I.

Reñaca

Simposio; International Symposium: Mechanisms of Cell Death: Molecular Insights and Therapeutic perspectives.; 2005

Autophagy is a distinct type (Type II) of Programmed Cell Death characterized by the accumulation of autophagic vacuoles. During autophagy, parts of the cytoplasm and organelles are encapsulated in double membrane vacuoles called autophagosomes, which finally fuse with lysosomes to degrade the incorporated material. Several signaling complexes and pathways are involved in the development of an autophagic response. Autophagy is stimulated by cellular signals such as starvation that inhibit the kinase Tor and by activation of PI3kinase type III. Important advances have been recently achieved to elucidate the molecules implicated in autophagy. Two protein conjugation systems are key components involved in the initial steps of the autophagic pathway: the Atg12-Atg5 conjugation and the Atg8/LC3 system. LC3 is conjugated to the lipid phosphatidylethanolamine and changes its distribution localizing to both the outer and inner autophagosomal membranes. We have presented evidence indicating that members of the Rab family of GTPases such as Rab24 and Rab7 are involved in the autophagic pathway. Rab24 localizes with LC3 upon induction of autophagy by starvation or rapamycin treatment and seems to be associated with formation of autophagosomes.   Rab7 localizes on the limiting membrane of autophagic vacuoles and is required for autophagic vacuole maturation since a functional Rab7 is required for fusion with the lysosomal compartment to degrade the incorporated material. Autophagy is not only involved in degradation but also is an essential cellular mechanism implicated in several other processes such as cell death, development and aging. We have recently shown that autophagy inhibits BCG and Mycobacterium tuberculosis survival in infected macrophages representing an underappreciated innate immunity mechanism used by the host cells to eliminate intracellular pathogens. On the other hand, we have also shown that autophagy induction favors the generation and maturation of the Coxiella burnetii-parasitophorous vacuole. Our results indicate that overexpression of proteins involved in the autophagic pathway such as LC3 and Rab24 promotes the generation of the Coxiella replicative niche and that transit through this pathway is beneficial for the intracellular survival of this bacterium. Therefore, autophagy can act as a defense mechanism against invasion by certain bacteria and virus, but also can be subverted by pathogens to establish a replicative niche.