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Cystathione β-synthase regulates HIF-1α stability through persulfidation of PHD2

The stringent expression of the hypoxia inducible factor-1α (HIF-1α) is critical to a variety of pathophysiological conditions. We reveal that, in normoxia, enzymatic action of cystathionine β-synthase (CBS) produces H(2)S, which persulfidates prolyl hydroxylase 2 (PHD2) at residues Cys(21) and Cys(...

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Autores principales: Dey, Anindya, Prabhudesai, Shubhangi, Zhang, Yushan, Rao, Geeta, Thirugnanam, Karthikeyan, Hossen, Md. Nazir, Dwivedi, Shailendra Kumar Dhar, Ramchandran, Ramani, Mukherjee, Priyabrata, Bhattacharya, Resham
Formato: Online Artículo Texto
Lenguaje:English
Publicado: American Association for the Advancement of Science 2020
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7458453/
https://www.ncbi.nlm.nih.gov/pubmed/32937467
http://dx.doi.org/10.1126/sciadv.aaz8534
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author Dey, Anindya
Prabhudesai, Shubhangi
Zhang, Yushan
Rao, Geeta
Thirugnanam, Karthikeyan
Hossen, Md. Nazir
Dwivedi, Shailendra Kumar Dhar
Ramchandran, Ramani
Mukherjee, Priyabrata
Bhattacharya, Resham
author_facet Dey, Anindya
Prabhudesai, Shubhangi
Zhang, Yushan
Rao, Geeta
Thirugnanam, Karthikeyan
Hossen, Md. Nazir
Dwivedi, Shailendra Kumar Dhar
Ramchandran, Ramani
Mukherjee, Priyabrata
Bhattacharya, Resham
author_sort Dey, Anindya
collection PubMed
description The stringent expression of the hypoxia inducible factor-1α (HIF-1α) is critical to a variety of pathophysiological conditions. We reveal that, in normoxia, enzymatic action of cystathionine β-synthase (CBS) produces H(2)S, which persulfidates prolyl hydroxylase 2 (PHD2) at residues Cys(21) and Cys(33) (zinc finger motif), augmenting prolyl hydroxylase activity. Depleting endogenous H(2)S either by hypoxia or by inhibiting CBS via chemical or genetic means reduces persulfidation of PHD2 and inhibits activity, preventing hydroxylation of HIF-1α, resulting in stabilization. Our in vitro findings are further supported by the depletion of CBS in the zebrafish model that exhibits axis defects and abnormal intersegmental vessels. Exogenous H(2)S supplementation rescues both in vitro and in vivo phenotypes. We have identified the persulfidated residues and defined their functional significance in regulating the activity of PHD2 via point mutations. Thus, the CBS/H(2)S/PHD2 axis may provide therapeutic opportunities for pathologies associated with HIF-1α dysregulation in chronic diseases.
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spelling pubmed-74584532020-09-16 Cystathione β-synthase regulates HIF-1α stability through persulfidation of PHD2 Dey, Anindya Prabhudesai, Shubhangi Zhang, Yushan Rao, Geeta Thirugnanam, Karthikeyan Hossen, Md. Nazir Dwivedi, Shailendra Kumar Dhar Ramchandran, Ramani Mukherjee, Priyabrata Bhattacharya, Resham Sci Adv Research Articles The stringent expression of the hypoxia inducible factor-1α (HIF-1α) is critical to a variety of pathophysiological conditions. We reveal that, in normoxia, enzymatic action of cystathionine β-synthase (CBS) produces H(2)S, which persulfidates prolyl hydroxylase 2 (PHD2) at residues Cys(21) and Cys(33) (zinc finger motif), augmenting prolyl hydroxylase activity. Depleting endogenous H(2)S either by hypoxia or by inhibiting CBS via chemical or genetic means reduces persulfidation of PHD2 and inhibits activity, preventing hydroxylation of HIF-1α, resulting in stabilization. Our in vitro findings are further supported by the depletion of CBS in the zebrafish model that exhibits axis defects and abnormal intersegmental vessels. Exogenous H(2)S supplementation rescues both in vitro and in vivo phenotypes. We have identified the persulfidated residues and defined their functional significance in regulating the activity of PHD2 via point mutations. Thus, the CBS/H(2)S/PHD2 axis may provide therapeutic opportunities for pathologies associated with HIF-1α dysregulation in chronic diseases. American Association for the Advancement of Science 2020-07-03 /pmc/articles/PMC7458453/ /pubmed/32937467 http://dx.doi.org/10.1126/sciadv.aaz8534 Text en Copyright © 2020 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works. Distributed under a Creative Commons Attribution NonCommercial License 4.0 (CC BY-NC). https://creativecommons.org/licenses/by-nc/4.0/ https://creativecommons.org/licenses/by-nc/4.0/This is an open-access article distributed under the terms of the Creative Commons Attribution-NonCommercial license (https://creativecommons.org/licenses/by-nc/4.0/) , which permits use, distribution, and reproduction in any medium, so long as the resultant use is not for commercial advantage and provided the original work is properly cited.
spellingShingle Research Articles
Dey, Anindya
Prabhudesai, Shubhangi
Zhang, Yushan
Rao, Geeta
Thirugnanam, Karthikeyan
Hossen, Md. Nazir
Dwivedi, Shailendra Kumar Dhar
Ramchandran, Ramani
Mukherjee, Priyabrata
Bhattacharya, Resham
Cystathione β-synthase regulates HIF-1α stability through persulfidation of PHD2
title Cystathione β-synthase regulates HIF-1α stability through persulfidation of PHD2
title_full Cystathione β-synthase regulates HIF-1α stability through persulfidation of PHD2
title_fullStr Cystathione β-synthase regulates HIF-1α stability through persulfidation of PHD2
title_full_unstemmed Cystathione β-synthase regulates HIF-1α stability through persulfidation of PHD2
title_short Cystathione β-synthase regulates HIF-1α stability through persulfidation of PHD2
title_sort cystathione β-synthase regulates hif-1α stability through persulfidation of phd2
topic Research Articles
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7458453/
https://www.ncbi.nlm.nih.gov/pubmed/32937467
http://dx.doi.org/10.1126/sciadv.aaz8534
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