Journal
BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS
Volume 557, Issue -, Pages 280-287Publisher
ACADEMIC PRESS INC ELSEVIER SCIENCE
DOI: 10.1016/j.bbrc.2021.04.035
Keywords
Diabetic retinopathy (DR); Transthyretin (TTR); Heterogeneous nuclear ribonucleoprotein; Human retinal microvascular endothelial; cells (hRECs)
Categories
Funding
- National Natural Science Foundation of China [81970819]
- China Postdoctoral Science Foundation [2020M671541]
- Youth Medical Talent Project of Jiangsu Province [QNRC2016182]
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Transthyretin (TTR) has been shown to suppress neovascularization in diabetic retinopathy by regulating molecules in the STAT-4/miR-223-3p/FBXW7 pathway. The study identified the interaction between TTR and hnRNPA2B1 in retinal microvascular endothelial cells, and proposed a TTR-hnRNPA2B1/STAT-4/miR-223-3p/FBXW7 pathway, providing a theoretical basis for clinical applications.
Transthyretin (TTR) has been proved to repress neovascularization in diabetic retinopathy environment by regulating the molecules in and downstream of the STAT-4/miR-223-3p/FBXW7 signal pathway; however, the details of its direct targets are still not well understood. The interaction between TTR and a target in nucleus of human retinal microvascular endothelial cells (hRECs), heterogeneous nuclear ribonucleoprotein (hnRNP) A2B1, was screened by immunoprecipitation (IP) and mass spectrum (MS), and it was further confirmed by co-immunoprecipitation (co-IP). Regarding ZDOCK analysis using Discovery Studio, the interface and potential binding sites between TTR and hnRNPA2B1 were simulated; mutants were designed in these regions and five soluble ones were recombinantly expressed and prepared; the interaction between TTR and hnRNPA2B1 were disrupted by several mutated residues. In addition, for several mutated TTRs, the inhibition activities against the proliferation, migration and tube formation of hRECs were absent in vitro. Following the disruption of TTR-hnRNPA2B1, the molecules in and downstream of STAT-4/miR-223-3p/FBXW7 signal pathway, including STAT-4, miR-223-3p, FBXW7 p-Akt and Notch1 could not be regulated by TTR mutants; therefore, a TTR-hnRNPA2B1/STAT-4/miR-223-3p/FBXW7 was proposed. In conclusion, this work suggested that TTR should play a physiological role in diabetic environment by the direct binding with hnRNPA2B1, and it provided a theoretical basis for clinical diagnosis, therapy and further application. (c) 2021 Elsevier Inc. All rights reserved.
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