ULK1ULK2

ULK1 and ULK2 are serine/threonine kinases of the UNC-51-like kinase family in humans. They are homologs of the C. elegans UNC-51 protein and act at the start of autophagy, a catabolic process that degrades cellular components. Together with the adaptor proteins ATG13, FIP200 (RB1CC1), and ATG101, ULK1 and ULK2 form the ULK complex, a key initiation module that triggers phagophore formation at sites of autophagosome biogenesis.

Regulation of the ULK complex depends on nutrient and energy status. mTORC1 inhibits ULK1 by phosphorylation under nutrient-rich conditions, while AMPK activates ULK1 in response to energy or nutrient stress. ULK2 is closely related and can participate in the same complex; in some contexts ULK2 can partially compensate for loss of ULK1, reflecting functional redundancy between the two kinases.

Functions of ULK1 and ULK2 include initiating autophagy by activating downstream ATG proteins and promoting membrane nucleation and expansion. The ULK complex is involved in various forms of autophagy, including mitophagy and selective autophagy, contributing to cellular homeostasis, development, and stress responses.

Clinical relevance of ULK1/ULK2 relates to the role of autophagy in cancer, neurodegenerative diseases, and metabolic disorders. Modulators targeting ULK1 are being explored for therapeutic potential, with outcomes that depend on context and tissue type.

Genetics and localization: ULK1 and ULK2 are broadly expressed in human tissues and function mainly in the cytoplasm, coordinating with the autophagy machinery during autophagosome formation. The two kinases share substantial sequence similarity and substrate preference, enabling partial redundancy in autophagy initiation.