Aminoacyl-Transfer RNA Synthetase Deficiency Promotes Angiogenesis via the Unfolded Protein Response Pathway

Arteriosclerosis, Thrombosis, and Vascular Biology
Daniel CastranovaBrant M Weinstein

Abstract

Understanding the mechanisms regulating normal and pathological angiogenesis is of great scientific and clinical interest. In this report, we show that mutations in 2 different aminoacyl-transfer RNA synthetases, threonyl tRNA synthetase (tars(y58)) or isoleucyl tRNA synthetase (iars(y68)), lead to similar increased branching angiogenesis in developing zebrafish. The unfolded protein response pathway is activated by aminoacyl-transfer RNA synthetase deficiencies, and we show that unfolded protein response genes atf4, atf6, and xbp1, as well as the key proangiogenic ligand vascular endothelial growth factor (vegfaa), are all upregulated in tars(y58) and iars(y68) mutants. Finally, we show that the protein kinase RNA-like endoplasmic reticulum kinase-activating transcription factor 4 arm of the unfolded protein response pathway is necessary for both the elevated vegfaa levels and increased angiogenesis observed in tars(y58) mutants. Our results suggest that endoplasmic reticulum stress acts as a proangiogenic signal via unfolded protein response pathway-dependent upregulation of vegfaa.

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Citations

Mar 13, 2017·Biochemical and Biophysical Research Communications·Hongcheng WangDeqin Yang
Sep 29, 2017·Arteriosclerosis, Thrombosis, and Vascular Biology·Jacqueline S DronRobert A Hegele
Mar 25, 2016·Arteriosclerosis, Thrombosis, and Vascular Biology·Karen M Lounsbury, Christopher S Francklyn
Jul 9, 2016·Nature Communications·Mao WangStuart A Cook
Oct 26, 2018·Arteriosclerosis, Thrombosis, and Vascular Biology·Hong S LuAlan Daugherty
May 28, 2019·Frontiers in Cell and Developmental Biology·Ashley WaldronAlicia Ebert

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