ULK1 targets Beclin-1 in autophagy

Abstract

The substrates of mammalian ULK1/2 and its yeast homologue Atg1 in autophagy have remained elusive. The class III phosphatidylinositol 3-kinase component Beclin-1 has now been identified as a physiological substrate of the ULK kinases in autophagy following amino acid starvation, therefore suggesting a critical molecular link between the upstream kinases and the autophagy core machinery.

Figure 1

ULK kinases activate the class III PI(3)K in autophagy following amino acid starvation and nutrient limitation. ULK kinases are positively regulated by AMPK following energy crisis and negatively regulated by the TORC1 kinase and/or unknown phosphatases following amino acid shortage. Guan and colleagues show that following amino acid deprivation or mTORC1 inhibition, active ULK activates VPS34 by phosphorylating ATG14L-bound Beclin-1 at Ser 14, an event that is required for PtdIns3P production and localization of the core autophagic machinery to phagophores and autophagosomes. Following nutrient limitation, AMPK activates VPS34 by phosphorylation of ATG14L-bound Beclin-1 at Ser 91 and Ser 94. It is also possible that other unknown targets of ULK (Atg1 in yeast) exist.