Endoglin Regulation of Smad2 Function Mediates Beclin1 Expression and Endothelial Autophagy

• Published in: The Journal of biological chemistry Vol. 290; no. 24; pp. 14884 - 14892
• Main Authors: Pan, Christopher C., Kumar, Sanjay, Shah, Nirav, Bloodworth, Jeffrey C., Hawinkels, Lukas J.A.C., Mythreye, Karthikeyan, Hoyt, Dale G., Lee, Nam Y.
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 12.06.2015; American Society for Biochemistry and Molecular Biology
• Subjects: angiogenesis; Animals; Apoptosis Regulatory Proteins - metabolism; autophagy; Autophagy - physiology; Base Sequence; Beclin-1; Cells, Cultured; Chromatin Immunoprecipitation; DNA Primers; Endoglin; endothelial cell; Endothelium - cytology; Endothelium - metabolism; Intracellular Signaling Peptides and Proteins - physiology; Mice; Real-Time Polymerase Chain Reaction; Reverse Transcriptase Polymerase Chain Reaction; Signal Transduction; SMAD transcription factor; Smad2 Protein - genetics; Smad2 Protein - physiology; transforming growth factor beta (TGF-β); SMAD transcription factor; autophagy; transforming growth factor beta (TGF-β); angiogenesis; endothelial cell
• ISSN: 0021-9258; 1083-351X
• DOI: 10.1074/jbc.M114.630178

Autophagy is the targeted degradation of proteins and organelles critical for homeostasis and cell survival. Transforming growth factor β (TGF-β) differentially regulates autophagy in a context-specific manner, although the precise intracellular mechanisms remain less clear. Importantly, how TGF-β controls autophagic responses in endothelial cells (EC) during angiogenesis is unknown. Here we identified endoglin, an EC-specific TGF-β co-receptor essential for angiogenesis, as a key determinant of autophagy. Among the two opposing TGF-β Smad pathways in the EC system (Smad1/5/8 and Smad2/3), we found Smad2 as the major transcriptional regulator of autophagy that targets beclin1 (BECN1) gene expression. Smad2, but not Smad3, acts as a repressor upstream of the BECN1 promoter region. Overall, endoglin promotes autophagy by impeding Smad2 transcriptional repressor activity. Notably, increased beclin1 levels upon Smad2 knockdown directly correlated with enhanced autophagy during angiogenesis. Taken together, these results establish endoglin as a critical mediator of autophagy and demonstrate a new transcriptional mechanism by which Smad2 inhibits angiogenesis. Background: Endoglin is a key regulator of TGF-β signaling in endothelial cells but its role in autophagy during angiogenesis is unknown. Results: Endoglin relieves Smad2-dependent BECN1 repression. Conclusion: Endoglin promotes autophagy during angiogenesis by regulating Smad2 function. Significance: Endoglin-mediated autophagy may be an effective vascular target.