Endoglin Regulation of Smad2 Function Mediates Beclin1 Expression and Endothelial Autophagy.
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.
From the Division of Pharmacology, College of Pharmacy.
Christopher C
CC
Pan
From the Division of Pharmacology, College of Pharmacy.
Sanjay
S
Kumar
From the Division of Pharmacology, College of Pharmacy.
Nirav
N
Shah
Loyola University Medical Center, Loyola University, Maywood, Illinois 60153, and.
Jeffrey C
JC
Bloodworth
Department of Molecular Cell Biology, Leiden University Medical Center, Leiden University, Leiden, The Netherlands.
Lukas J A C
LJ
Hawinkels
Department of Chemistry and Biochemistry, University of South Carolina, Columbia, South Carolina 29208.
Karthikeyan
K
Mythreye
From the Division of Pharmacology, College of Pharmacy.
Dale G
DG
Hoyt
From the Division of Pharmacology, College of Pharmacy, Davis Heart and Lung Research Institute, and James Comprehensive Cancer Center, Ohio State University, Columbus, Ohio 43210, lee.5064@osu.edu.
Nam Y
NY
Lee
D000818:Animals; D051017:Apoptosis Regulatory Proteins / Q000378:metabolism*; D001343:Autophagy / Q000502:physiology*; D001483:Base Sequence; D000071186:Beclin-1; D002478:Cells, Cultured; D047369:Chromatin Immunoprecipitation; D017931:DNA Primers; D000071063:Endoglin; D004727:Endothelium / Q000166:cytology / Q000378:metabolism*; D047908:Intracellular Signaling Peptides and Proteins / Q000502:physiology*; D051379:Mice; D060888:Real-Time Polymerase Chain Reaction; D020133:Reverse Transcriptase Polymerase Chain Reaction; D051899:Smad2 Protein / Q000235:genetics / Q000502:physiology*
D051017:Apoptosis Regulatory Proteins; D000071186:Beclin-1; C115010:Becn1 protein, mouse; D017931:DNA Primers; D000071063:Endoglin; C502004:Eng protein, mouse; D047908:Intracellular Signaling Peptides and Proteins; D051899:Smad2 Protein; C497783:Smad2 protein, mouse
SMAD transcription factor; angiogenesis; autophagy; endothelial cell; transforming growth factor beta (TGF-β)