Figure 1.

Model for the role of DENND3 in the autophagic response based on Xu et al. (8). DENND3 is first phosphorylated by ULK1, increasing its GEF activity toward Rab12 and promoting Rab12 binding. ULK also activates the myosin light chain kinase (MLCK)-like protein, spaghetti-squash activator (Sqa), which in turn activates myosin IIA. DENND3 is also phosphorylated at Tyr-940 by an as yet unknown kinase, leading to an open and active conformation; this also exposes an actin-binding surface. ULK1-activated myosin IIA binds the Rab12–DENND3–actin complex in the growing phagophore, enabling autophagosome translocation over microfilaments. After maturation, autophagosomes fuse with lysosomes, and their contents are degraded and recycled back to the cytosol.