Regulation and Function of Uncoordinated-51 Like Kinase Proteins

Significance: The Atg1/ULK1 (uncoordinated-51 like kinase 1) protein complex plays an essential role regulating autophagy in mammalian cells. As autophagy is implicated in normal cellular homeostasis and multiple diseases, better mechanistic insight drives development of novel therapeutic approaches. Recent Advances: Multiple independent laboratories have contributed important new insights into the ULK-signalling pathway. ULK1/2 function is regulated by mTOR complex 1 and AMPK through a network of phosphorylation events. ULK signalling controls autophagosome formation in conjunction with other key regulatory factors such as Beclin1 and Atg9. Critical Issues: From recent work, we have gained a better understanding of ULK proteins and their functional roles but details still need to be resolved. A combination of approaches has been used to better elucidate the sub-classes of autophagy that are differentially dependent upon ULK family members. Roles of ULK members in autophagy-independent trafficking and signalling pathways have also been better defined, highlighting the diversity of functions coordinated by this protein family. Future Directions: As mechanisms and in vivo functions become clarified for the different ULK members, more robust strategies for targeting these essential autophagy kinases can be developed. Antioxid. Redox Signal. 17, 775-785.