Inhibition of ULK2 Autophagic Activity by Its Association with YAP

Uncoordinated 51-like kinase 2 (ULK2) is a member of the serine/threonine kinase family that function s an essential role regulating autophagy in mammalian cells. As autophagy is implicated in normal cellular homeostasis and multiple diseases, better mechanistic insight will drive the development of novel therapeutic approaches. Here, we present evidence that ULK2 interacts with YAP for its degradation and subcellular localization. A potential PPxY motif ( 328 PPnY 331 ) was identified, which is similar with the consensus PPxY motif in ULK2 S/P domain. The P329A (PA) mutation in the PY motif of ULK2 abolished the YAP-ULK2 association. At first, we observed that ULK2 physically interacted to  YAP in vivo and in vitro, using a pull-down approach. Secondly, ULK2 and YAP co- localized at the apical (or tight junction) membrane as visualized by confocal microscopy. Furthermore, the PA mutant substantially increased during autophagy than that of wild-type ULK2 or the P242A mutant in transient transfection assays. Thus, the association between ULK2 and YAP through the WW domain links autophagy and the Hippo signal transduction pathway.