FIH Regulates Cellular Metabolism through Hydroxylation of the Deubiquitinase OTUB1.
The asparagine hydroxylase, factor inhibiting HIF (FIH), confers oxygen-dependence upon the hypoxia-inducible factor (HIF), a master regulator of the cellular adaptive response to hypoxia. Studies investigating whether asparagine hydroxylation is a general regulatory oxygen-dependent modification ha...
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| Main Authors: | , , , , , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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Public Library of Science (PLoS)
2016-01-01
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| Series: | PLoS Biology |
| Online Access: | https://doi.org/10.1371/journal.pbio.1002347 |
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| author | Carsten C Scholz Javier Rodriguez Christina Pickel Stephen Burr Jacqueline-Alba Fabrizio Karen A Nolan Patrick Spielmann Miguel A S Cavadas Bianca Crifo Doug N Halligan James A Nathan Daniel J Peet Roland H Wenger Alex Von Kriegsheim Eoin P Cummins Cormac T Taylor |
| author_facet | Carsten C Scholz Javier Rodriguez Christina Pickel Stephen Burr Jacqueline-Alba Fabrizio Karen A Nolan Patrick Spielmann Miguel A S Cavadas Bianca Crifo Doug N Halligan James A Nathan Daniel J Peet Roland H Wenger Alex Von Kriegsheim Eoin P Cummins Cormac T Taylor |
| author_sort | Carsten C Scholz |
| collection | DOAJ |
| description | The asparagine hydroxylase, factor inhibiting HIF (FIH), confers oxygen-dependence upon the hypoxia-inducible factor (HIF), a master regulator of the cellular adaptive response to hypoxia. Studies investigating whether asparagine hydroxylation is a general regulatory oxygen-dependent modification have identified multiple non-HIF targets for FIH. However, the functional consequences of this outside of the HIF pathway remain unclear. Here, we demonstrate that the deubiquitinase ovarian tumor domain containing ubiquitin aldehyde binding protein 1 (OTUB1) is a substrate for hydroxylation by FIH on N22. Mutation of N22 leads to a profound change in the interaction of OTUB1 with proteins important in cellular metabolism. Furthermore, in cultured cells, overexpression of N22A mutant OTUB1 impairs cellular metabolic processes when compared to wild type. Based on these data, we hypothesize that OTUB1 is a target for functional hydroxylation by FIH. Additionally, we propose that our results provide new insight into the regulation of cellular energy metabolism during hypoxic stress and the potential for targeting hydroxylases for therapeutic benefit. |
| format | Article |
| id | doaj-art-195eb6b4e4534a8d981fea77cbdb36dd |
| institution | Kabale University |
| issn | 1544-9173 1545-7885 |
| language | English |
| publishDate | 2016-01-01 |
| publisher | Public Library of Science (PLoS) |
| record_format | Article |
| series | PLoS Biology |
| spelling | doaj-art-195eb6b4e4534a8d981fea77cbdb36dd2025-08-20T03:46:42ZengPublic Library of Science (PLoS)PLoS Biology1544-91731545-78852016-01-01141e100234710.1371/journal.pbio.1002347FIH Regulates Cellular Metabolism through Hydroxylation of the Deubiquitinase OTUB1.Carsten C ScholzJavier RodriguezChristina PickelStephen BurrJacqueline-Alba FabrizioKaren A NolanPatrick SpielmannMiguel A S CavadasBianca CrifoDoug N HalliganJames A NathanDaniel J PeetRoland H WengerAlex Von KriegsheimEoin P CumminsCormac T TaylorThe asparagine hydroxylase, factor inhibiting HIF (FIH), confers oxygen-dependence upon the hypoxia-inducible factor (HIF), a master regulator of the cellular adaptive response to hypoxia. Studies investigating whether asparagine hydroxylation is a general regulatory oxygen-dependent modification have identified multiple non-HIF targets for FIH. However, the functional consequences of this outside of the HIF pathway remain unclear. Here, we demonstrate that the deubiquitinase ovarian tumor domain containing ubiquitin aldehyde binding protein 1 (OTUB1) is a substrate for hydroxylation by FIH on N22. Mutation of N22 leads to a profound change in the interaction of OTUB1 with proteins important in cellular metabolism. Furthermore, in cultured cells, overexpression of N22A mutant OTUB1 impairs cellular metabolic processes when compared to wild type. Based on these data, we hypothesize that OTUB1 is a target for functional hydroxylation by FIH. Additionally, we propose that our results provide new insight into the regulation of cellular energy metabolism during hypoxic stress and the potential for targeting hydroxylases for therapeutic benefit.https://doi.org/10.1371/journal.pbio.1002347 |
| spellingShingle | Carsten C Scholz Javier Rodriguez Christina Pickel Stephen Burr Jacqueline-Alba Fabrizio Karen A Nolan Patrick Spielmann Miguel A S Cavadas Bianca Crifo Doug N Halligan James A Nathan Daniel J Peet Roland H Wenger Alex Von Kriegsheim Eoin P Cummins Cormac T Taylor FIH Regulates Cellular Metabolism through Hydroxylation of the Deubiquitinase OTUB1. PLoS Biology |
| title | FIH Regulates Cellular Metabolism through Hydroxylation of the Deubiquitinase OTUB1. |
| title_full | FIH Regulates Cellular Metabolism through Hydroxylation of the Deubiquitinase OTUB1. |
| title_fullStr | FIH Regulates Cellular Metabolism through Hydroxylation of the Deubiquitinase OTUB1. |
| title_full_unstemmed | FIH Regulates Cellular Metabolism through Hydroxylation of the Deubiquitinase OTUB1. |
| title_short | FIH Regulates Cellular Metabolism through Hydroxylation of the Deubiquitinase OTUB1. |
| title_sort | fih regulates cellular metabolism through hydroxylation of the deubiquitinase otub1 |
| url | https://doi.org/10.1371/journal.pbio.1002347 |
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