Autophagy maintains cellular homeostasis in response to various stresses, including nutrient starvation. Vps34, a PtdIns-3-OH kinase, induces autophagy but also has non-autophagy-related functions. How Vps34 can exert these different roles has been unclear.

Guan and colleagues (Cell 152, 290–303; 2013 ) studied the regulation of Vps34 following glucose starvation by isolating four different Vps34 sub-groups, which were divided into non-autophagy and pro-autophagy complexes. They show that following energy deprivation, the known nutrient sensor AMPK (AMP-activated protein kinase) regulates the activity of Vps34 complexes either by inhibiting non-autophagy complexes or by activating pro-autophagy complexes. By phosphorylating Vps34 in the non-autophagy complex, AMPK suppresses overall PtdIns(3)P production, which protects the cells from starvation. In contrast, during starvation, AMPK phosphorylates Beclin-1 in the pro-autophagy complex (which also contains the Beclin-1-binding protein ATG14L) to induce autophagy. Interestingly, ATG14L suppresses AMPK-mediated phosphorylation of Vps34 in this complex, resulting in an increased level of the autophagy-related pool of PtdIns(3)P. This indicates that distinct Vps34 complexes are regulating the level of PtdIns(3)P in different cellular compartments. Thus, through differential regulation of Vps34 complexes, AMPK can optimize the cellular response to nutrient stress.