PT  - JOURNAL ARTICLE
AU  - Maria Zachari
AU  - Marianna Longo
AU  - Ian G Ganley
TI  - Aberrant autophagosome formation occurs upon small molecule inhibition of ULK1 kinase activity
AID  - 10.26508/lsa.202000815
DP  - 2020 Dec 01
TA  - Life Science Alliance
PG  - e202000815
VI  - 3
IP  - 12
4099  - https://www.life-science-alliance.org/content/3/12/e202000815.short
4100  - https://www.life-science-alliance.org/content/3/12/e202000815.full
SO  - Life Sci. Alliance2020 Dec 01; 3
AB  - Autophagy is a crucial homeostatic mechanism that mediates the degradation of damaged or excess intracellular components. Such components are engulfed and sequestered into double membrane autophagosomes, which deliver their contents to lysosomes for degradation. Autophagy plays a role in numerous human disorders and its pharmacological targeting by small molecules offers therapeutic potential. The serine/threonine kinase ULK1 (and its homologue ULK2) is the most upstream component of the autophagic machinery and is required for autophagy initiation. Here, we use the most selective and potent published ULK1 inhibitors to gain insights into ULK1 kinase function during autophagy. Treatment with all inhibitors blocked autophagy but also resulted in the limited formation of initial autophagosome-like structures, which appeared abnormal in size and did not traffic to lysosomes. We found that upon ULK1 inhibition, phosphatidylinositol-3-phosphate–binding proteins are still recruited to forming autophagosomes, implying that ULK1 activity is not essential for VPS34 activation. We conclude that the kinase activity of ULK1 is important in regulating autophagosome maturation, by the phosphorylation of currently unidentified key substrates.