Physiological functions of ULK1/2

UNC-51-like kinases 1 and 2 (ULK1/2) are serine/threonine kinases that are best known for their evolutionarily conserved role in the autophagy pathway. Upon sensing the nutrient status of a cell, ULK1/2 integrate signals from upstream cellular energy sensors such as mTOR and AMPK and relay them to the downstream components of the autophagy machinery. ULK1/2 also play indispensable roles in the selective autophagy pathway, removing damaged mitochondria, invading pathogens, and toxic protein aggregates. Additional functions of ULK1/2 have emerged beyond autophagy, including roles in protein trafficking, RNP granule dynamics, and signaling events impacting innate immunity, axon guidance, cellular homeostasis, and cell fate. Therefore, it is no surprise that alterations in ULK1/2 expression and activity have been linked with pathophysiological processes, including cancer, neurological disorders, and cardiovascular diseases. Growing evidence suggests that ULK1/2 function as biological rheostats, tuning cellular functions to intra and extra-cellular cues. Given their broad physiological relevance, ULK1/2 are candidate targets for small molecule activators or inhibitors that may pave the way for the development of therapeutics for the treatment of diseases in humans. (c) 2024 The Authors. Published by Elsevier Ltd.