Meta-Biol

• Pathways

ULK1 is a serine-threonine kinase with key roles in macroautophagy in response to starvation. Under high nutrient conditions, ULK1 is phosphorylated by mTORC1, inhibiting the autophagy pathway, while under nutrient-limited conditions, mTORC1 phosphorylation is replaced by AMPK-mediated phosphorylation, resulting in the activation of both ULK1 and the autophagy pathway (reviewed in Wong et al, 2013). How nutrient levels are sensed by mTORC1 and ULK1 is not fully established, but a number of recent papers have highlighted a role for RAB proteins and their regulators in autophagy (Matsui and Fukuda, 2013; Matsui et al, 2014; Xu et al, 2015; Fan et al, 2016; reviewed in Lamb et al, 2013; Xu and McPherson, 2015). Under starvation conditions, ULK1 phosphorylates DENND3, a RAB12 GEF, at serine residues 472 and 490, activating it and promoting the formation of GTP-bound RAB12 (Yoshimura et al, 2010; Xu et al, 2015). Active RAB12 promotes the constitutive recycling or degradation of a number of plasma membrane proteins including the amino acid transporter SLC36A4 (also known as PAT4). Degradation of SLC36A4 decreases the intracellular amino acid concentration, inactivating mTORC1 and promoting the macroautophagy pathway (Matsui et al, 2011; Matsui and Fukuda, 2013; Xu et al, 2015; Fan et al, 2016).