Figure 1. Model showing the RAPGEF3-dependent pathway involved in the control of autophagy and the molecules involved in the autophagic response induced by Staphylococcus aureus. (A) Bacterial infections may modulate the levels of intracellular cAMP. When the levels of cAMP are increased, this can activate RAPGEF3, which through RAP2B and PLCE1/PLCε activation induces an increase in Ins(1,4,5)P3. In turn, this Ins(1,4,5)P3 increase leads to calcium release from the ER, which activates the calpain cysteine-proteases. These calpains are able to cleave ATG5 inhibiting the autophagic pathway. Thus, cAMP via calpains activation negatively regulates autophagy. (B) S. aureus is incorporated into the cell by phagocytosis. After the infection, S. aureus produces a decrease in the amount of active RAP2B, likely through the decline in the intracellular cAMP levels activating the autophagic pathway. The damage caused by the α-toxin Hla to the phagosomal membrane is likely responsible for the recruitment of LC3 to the phagosomal membrane of a subset of phagosomal-containing bacteria. Afterwards, the pathogen escapes into the cytoplasm to finally cause cell death, and spread to neighboring cells. Another group of bacteria recruits RAPGEF3 and/or RAP2B to the phagosome membrane.