Figure 1.

The multifaceted functions of human ATG4s. The canonical function of ATG4s is to process Atg8-family proteins to prime these proteins for lipidation onto phagophore membranes (1). However, during PINK1-PRKN mitophagy, ATG4s also regulate ATG9A trafficking to mitochondria via their proximal partners, ARFIP2 and LRBA, to promote ER-phagophore contacts which are established by ATG2-ATG9A. This function of ATG4s is independent of their protease activity and of Atg8-family proteins (2). ATG4s can function as deubiquitin-like enzymes to regulate levels of ATG8ylation through a process named de-ATG8ylation (3) but are not essential for the removal of lipidated Atg8-family proteins from autolysosomes (4)