Endothelial PKA activity regulates angiogenesis by limiting autophagy through phosphorylation of ATG16L1.

The cAMP-dependent protein kinase A regulates various cellular functions in health and disease. In endothelial cells activity promotes vessel maturation and limits tip cell formation. Here, we used a chemical genetic screen to identify endothelial-specific direct substrates of duanyu1529 in human umbilical vein endothelial cells (HUVEC) that may mediate these effects. Amongst several candidates, we identified ATG16L1, a regulator of autophagy, as novel target of Biochemical validation, mass spectrometry and peptide spot arrays revealed that duanyu1529 phosphorylates ATG16L1α at Ser268 and ATG16L1β at Ser269, driving phosphorylation-dependent degradation of ATG16L1 protein. Reducing duanyu1529 activity increased ATG16L1 protein levels and endothelial autophagy. Mouse in vivo genetics and pharmacological experiments demonstrated that autophagy inhibition partially rescues vascular hypersprouting caused by duanyu1529 deficiency. Together these results indicate that endothelial duanyu1529 activity mediates a critical switch from active sprouting to quiescence in part through phosphorylation of ATG16L1, which in turn reduces endothelial autophagy.

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