ULK1

ULK1 is a serine/threonine kinase and a key initiator of mammalian autophagy, functioning near the apex of a nutrient-sensitive regulatory pathway^[1]. Mechanistically, AMPK binds ULK1 and supports ULK1-mediated autophagy, while mTORC1 negatively regulates the ULK1 autophagic complex through phosphorylation-dependent control^[2][3]. During starvation, ULK1 links cellular energy sensing to downstream autophagy machinery, including ATG13, FIP200/RB1CC1, ATG101, ATG14L, VPS34, and phagophore formation^[3][4]. In disease models, altered ULK1 signaling has been connected with prostate cancer progression, prion infection, clear cell renal cell carcinoma, cardiomyocyte oxidative injury, and pathogen-related autophagy^{[5][6][7][8][9]}. Compared with ULK2, ULK1 shows strong functional overlap in nutrient-starvation autophagy, because combined ULK1/ULK2 loss disrupts autophagy activation more clearly than single loss^[10]. Compared with ULK3, ULK1 remains part of the canonical mTOR-AMPK autophagy axis, whereas ULK3 can support mTOR-insensitive autophagic flux in BIN1-deficient hippocampal neurons^[11]. For experimental applications, ULK1 pathway modulation can be studied with AMPK activators, mTOR inhibitors, deubiquitinase inhibitor WP1130, and pathway inhibitors targeting CAMKK2-AMPK-ULK1 signaling^[2][5][12].