Autophagy Pathways and Regulation

TOR

Beclin-1

ATG17

Lysosome

Autophagosome

Macroautophagy. Macroautophagy activation is under the control of multiple signaling mechanisms, two of which are shown in the above figure. In the presence of growth signals, TOR kinase suppresses autophagy initiation by inhibiting a kinase complex containing ATG17. In contrast, stress signals induce activation of Beclin-1 to trigger formation of the phagophore membrane which is likely derived from the endoplasmic reticulum (1). Many other autophagy proteins are then involved in the downstream process of creating and elongating the phagophore (2), joining the phagophore ends to complete the phagosome around cytoplasmic contents (3), and finally fusing the phagosome with the lysosome for degradation (4).

Microautophagy. Microautophagy refers to the direct engulfment of cytoplasmic content by the lysosome. There is evidence for several distinct types of microautophagy that differ based on the formation of the membrane, which can invaginate or protrude around cellular components. Similar to macroautophagy, microautophagy can be selective or non-selective, is able to degrade entire organelles, and can be activated by signals like environmental stress.

Chaperone-mediated Autophagy. Chaperone-mediated autophagy utilizes heat shock proteins and transporters on lysosomal membranes to degrade proteins that express a targeting motif, making it a highly specific process. The targeting motif is recognized by chaperones like HSPA8/HSC70, which transfer the protein to the lysosomal membrane. Upon binding with LAMP-2A on the lysosome, the target is internalized into the lysosomal lumen for degradation. Chaperone-mediated autophagy is regulated by environmental stress, and LAMP-2A expression levels can dictate the rate at which it occurs.

Tools for Studying Autophagy Pathways and Regulation