cAMP and EPAC Are Key Players in the Regulation of the Signal Transduction Pathway Involved in the α-Hemolysin

Autophagic Response

Mestre MB et al., PLoS Pathog. 2012; 8(5):e1002664.

Speaker: Ming-Zhang Lin (林明璋)                      Time: 13:00~14:00, Feb. 20, 2013

Commentator: Dr. Lien-I Hor (何漣漪老師)       Place: Room 601

Abstract

Staphylococcus aureus is a microorganism that causes serious infectious diseases such as pneumonia, endocarditis, osteomyelitis, and wound infections lead to host cell death. Recently, the researchers were indicated that after the infection, S. aureus localizes to autophagosomes and inhibits the process of maturation and fusion with lysosomes increase the intracellular bacterial survival rate and cause host cell death, spreading the infection. The author previously demonstrated that α-hemolysin (Hla), which is a pore-forming toxin secreted by S. aureus, is the factor responsible for the host autophagic response. This Hla-induced autophagic response is non-canonical pathway, which is Beclin1/PI3K-independent, but requires Atg5. This autophagic vesicles, which generated by the Hla are non-acidic and non-degradative compartments, indicating that somehow the Hla impedes the maturation of autophagic structures.  Thus, the authors interested in determining whether other pathways might be involved in the regulation of this ‘‘non-canonical’’ autophagic response. They indicated that cAMP is able to inhibition the autophagy induced by α-hemolysin but did not substantially affect starvation-induced autophagy, and that PKA the classical cAMP effector, dose not participate in this regulation. The author show that EPAC and Rap2b are downstream component of cAMP, through calpain activation to regulation of Hla-induced autophagy. Similar results were obtained in cells infected with different S. aureus strains, and treatment with cAMP could marked decrease S. aureus replication. That knowledge of the signal transduction mechanisms involved in the Hla-induced autophagy response will contribute to our understanding of the molecular mechanisms used by S. aureus to survive in infected cells, a key step in Staphylococcal pathogenicity.

References:

1.      Alpha-hemolysin is required for the activation of the autophagic pathway in Staphylococcus aureus infected cells. Mestre MB et al., (2010) Autophagy  6: 110–125

2.      Staphylococcus aureus subvert autophagy for induction of caspase-independent host cell death. Schnaith A et al., (2007) J Biol Chem 282: 2695–2706.