Autophagy starts with phagophore (also known as isolation membrane) formation, a step is initiated by a protein complex comprising UNC-51-like kinase 1 or 2 (ULK1 or ULK2) and Atg (autophagy-related genes) proteins. ULK1/2 then phosphorylates components of the class III phosphatidylinositol 3-kinase (PI3K) complex, whose formation is driven by Beclin 1. The phagophore elongates and isolates its cargo inside a closed structure termed autophagosome. The fusion of the lysosome with the autophagosome as an autophagolysosome (or autolysosome) allows the degradation of its contents.
InvivoGen provides a variety of small molecules to modulate autophagy through:
- Inhibition of mTOR activation
Several signaling pathways triggered by nutrient/growth factor levels converge to mTORc1 (aka mammalian target of rapamycin complex 1). mTORc1 is a major negative regulatory axis of autophagy. Thus, direct inhibitors of mTOR and those of pathways activating mTOR may be used to induce autophagy.
- Activation of the autophagosome formation
As the autophagosome formation is Beclin 1-dependent, it can be indirectly activated using inhibitors of natural inhibitors of Beclin 1. For example, Beclin1 being negatively regulated by caspases, the use of caspase inhibitors allows the initial stages of autophagy. Furthermore, inhibition of the 26S proteasome results in the stabilization of Atg protein levels, thus promoting the autophagy process.
- Inhibition of autophagosome / autophagolysosome formation
The autophagosome formation can be inhibited by targeting positive regulators of the ULK- and Beclin1-complexes, such as MAP kinases, JNK1, ERK, and p38.
The autophagolysosome formation can be inhibited by targeting molecules implicated in the endosomal acidification process.