Atg4D Activators

ATG4D can be classified based on their modes of action which ultimately converge on the process of autophagy, a cellular degradation pathway. Lithium chloride, SB 216763, and 6-BIO share a common mechanism of activating autophagy by inhibiting glycogen synthase kinase 3 (GSK-3). This inhibition is known to relieve the suppression on autophagy pathways, thereby facilitating the engagement of ATG4D in its role of processing the microtubule-associated protein 1A/1B-light chain 3 (LC3) – a critical step in autophagosome formation. Similarly, trehalose acts to activate autophagy, albeit through an mTOR-independent mechanism. Its unique action can lead to the activation of ATG4D by promoting the assembly of autophagosomes, necessary for autophagic flux. Spermidine contributes to this procession through the inhibition of acetyltransferase, which is another route to stimulate the autophagic machinery, subsequently engaging ATG4D in its proteolytic function.

Rapamycin, Torin 1, AICAR, metformin, and salicylate, initiates ATG4D activation through a different facet of the autophagy regulatory network. Rapamycin and Torin 1 exert their effect by directly inhibiting mTOR, a central regulator of cell growth and metabolism that negatively regulates autophagy. Inhibition of mTOR leads to the activation of the autophagy pathway, thereby necessitating the proteolytic action of ATG4D. AICAR and metformin activate AMP-activated protein kinase (AMPK), which in turn can initiate the autophagic process. Salicylate also activates AMPK but does so in a manner distinct from AICAR and metformin. The resulting activation of autophagy from these chemicals ensures the involvement of ATG4D in autophagosome maturation. Lastly, nicotinamide and resveratrol modulate sirtuins, a family of proteins implicated in cellular health, which can lead to autophagy induction and the subsequent activation of ATG4D, showcasing the diverse cellular signaling pathways that converge on the process of autophagy and the activation of ATG4D.