Promotion of TLR7-MyD88-dependent Inflammation and Autoimmunity through Stem-loop Changes in Lnc-Atg16l1
Ontology highlight
ABSTRACT:
ORGANISM(S): Mus musculus
PROVIDER: GSE228970 | GEO | 2024/10/12
REPOSITORIES: GEO
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Project description:The aim of this study is to survey global gene expression of total thymocytes from wild-type mice and Atg16l1 mutant (hypomorph) mice. Experiment Overall Design: Total RNA was extracted from total thymocytes from the following samples and analyzed: Experiment Overall Design: Atg16l1 hypomorph: 2 mice (7 weeks), 1 male and 1 female Experiment Overall Design: Control: 2 mice (7 weeks), 1 male and 1 female Experiment Overall Design: Global gene expression profiling was performed using Affymetrix technology. The animals used were independent of each other.
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Project description:The cAMP-dependent protein kinase A (PKA) regulates a plethora of cellular functions in health and disease. During angiogenesis, PKA activity in endothelial cells controls the transition from sprouting to vessel maturation and limits tip cell formation independently of Notch signaling. The molecular PKA targets mediating these effects remain unknown. We report a chemical genetics screen identifying endothelial-specific substrates of PKA in human umbilical vein endothelial cells (HUVEC). We identified ATG16L1, a regulator of autophagy, as novel target of PKA. Biochemical validation, mass spectrometry and peptide spot arrays revealed that PKA phosphorylates ATG16L1α at Ser268 and ATG16L1β at Ser269. The phosphorylations drive degradation of ATG16L1 protein. Knocking down PKA or inhibiting its activity increased ATG16L1 protein levels and endothelial autophagy. In vivo genetics and pharmacological experiments demonstrated that autophagy inhibition partially rescues vascular hypersprouting caused by PKA deficiency. We propose that endothelial PKA activity restricts active sprouting by reducing endothelial autophagy through phosphorylation of ATG16L1.
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