OTUB1 augments hypoxia signaling via its non-canonical ubiquitination inhibition of HIF-1α during hypoxia adaptation
Abstract As a main regulator of cellular responses to hypoxia, the protein stability of hypoxia-inducible factor (HIF)-1α is strictly controlled by oxygen tension dependent of PHDs-catalyzed protein hydroxylation and pVHL complex-mediated proteasomal degradation. Whether HIF-1α protein stability as...
| Main Authors: | , , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
| Published: |
Nature Publishing Group
2022-06-01
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| Series: | Cell Death and Disease |
| Online Access: | https://doi.org/10.1038/s41419-022-05008-z |
| _version_ | 1811227231341510656 |
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| author | Xing Liu Hongyan Deng Jinhua Tang Zixuan Wang Chunchun Zhu Xiaolian Cai Fangjing Rong Xiaoyun Chen Xueyi Sun Shuke Jia Gang Ouyang Wenhua Li Wuhan Xiao |
| author_facet | Xing Liu Hongyan Deng Jinhua Tang Zixuan Wang Chunchun Zhu Xiaolian Cai Fangjing Rong Xiaoyun Chen Xueyi Sun Shuke Jia Gang Ouyang Wenhua Li Wuhan Xiao |
| author_sort | Xing Liu |
| collection | DOAJ |
| description | Abstract As a main regulator of cellular responses to hypoxia, the protein stability of hypoxia-inducible factor (HIF)-1α is strictly controlled by oxygen tension dependent of PHDs-catalyzed protein hydroxylation and pVHL complex-mediated proteasomal degradation. Whether HIF-1α protein stability as well as its activity can be further regulated under hypoxia is not well understood. In this study, we found that OTUB1 augments hypoxia signaling independent of PHDs/VHL and FIH. OTUB1 binds to HIF-1α and depletion of OTUB1 reduces endogenous HIF-1α protein under hypoxia. In addition, OTUB1 inhibits K48-linked polyubiquitination of HIF-1α via its non-canonical inhibition of ubiquitination activity. Furthermore, OTUB1 promotes hypoxia-induced glycolytic reprogramming for cellular metabolic adaptation. These findings define a novel regulation of HIF-1α under hypoxia and demonstrate that OTUB1-mediated HIF-1α stabilization positively regulates HIF-1α transcriptional activity and benefits cellular hypoxia adaptation. |
| first_indexed | 2024-04-12T09:38:02Z |
| format | Article |
| id | doaj.art-a5928b296dac4baf9d4ad6f925b2d475 |
| institution | Directory Open Access Journal |
| issn | 2041-4889 |
| language | English |
| last_indexed | 2024-04-12T09:38:02Z |
| publishDate | 2022-06-01 |
| publisher | Nature Publishing Group |
| record_format | Article |
| series | Cell Death and Disease |
| spelling | doaj.art-a5928b296dac4baf9d4ad6f925b2d4752022-12-22T03:38:10ZengNature Publishing GroupCell Death and Disease2041-48892022-06-0113611210.1038/s41419-022-05008-zOTUB1 augments hypoxia signaling via its non-canonical ubiquitination inhibition of HIF-1α during hypoxia adaptationXing Liu0Hongyan Deng1Jinhua Tang2Zixuan Wang3Chunchun Zhu4Xiaolian Cai5Fangjing Rong6Xiaoyun Chen7Xueyi Sun8Shuke Jia9Gang Ouyang10Wenhua Li11Wuhan Xiao12State Key Laboratory of Freshwater Ecology and Biotechnology, Institute of Hydrobiology, Chinese Academy of SciencesCollege of Life Science, Wuhan UniversityState Key Laboratory of Freshwater Ecology and Biotechnology, Institute of Hydrobiology, Chinese Academy of SciencesState Key Laboratory of Freshwater Ecology and Biotechnology, Institute of Hydrobiology, Chinese Academy of SciencesState Key Laboratory of Freshwater Ecology and Biotechnology, Institute of Hydrobiology, Chinese Academy of SciencesState Key Laboratory of Freshwater Ecology and Biotechnology, Institute of Hydrobiology, Chinese Academy of SciencesState Key Laboratory of Freshwater Ecology and Biotechnology, Institute of Hydrobiology, Chinese Academy of SciencesState Key Laboratory of Freshwater Ecology and Biotechnology, Institute of Hydrobiology, Chinese Academy of SciencesState Key Laboratory of Freshwater Ecology and Biotechnology, Institute of Hydrobiology, Chinese Academy of SciencesState Key Laboratory of Freshwater Ecology and Biotechnology, Institute of Hydrobiology, Chinese Academy of SciencesState Key Laboratory of Freshwater Ecology and Biotechnology, Institute of Hydrobiology, Chinese Academy of SciencesCollege of Life Science, Wuhan UniversityState Key Laboratory of Freshwater Ecology and Biotechnology, Institute of Hydrobiology, Chinese Academy of SciencesAbstract As a main regulator of cellular responses to hypoxia, the protein stability of hypoxia-inducible factor (HIF)-1α is strictly controlled by oxygen tension dependent of PHDs-catalyzed protein hydroxylation and pVHL complex-mediated proteasomal degradation. Whether HIF-1α protein stability as well as its activity can be further regulated under hypoxia is not well understood. In this study, we found that OTUB1 augments hypoxia signaling independent of PHDs/VHL and FIH. OTUB1 binds to HIF-1α and depletion of OTUB1 reduces endogenous HIF-1α protein under hypoxia. In addition, OTUB1 inhibits K48-linked polyubiquitination of HIF-1α via its non-canonical inhibition of ubiquitination activity. Furthermore, OTUB1 promotes hypoxia-induced glycolytic reprogramming for cellular metabolic adaptation. These findings define a novel regulation of HIF-1α under hypoxia and demonstrate that OTUB1-mediated HIF-1α stabilization positively regulates HIF-1α transcriptional activity and benefits cellular hypoxia adaptation.https://doi.org/10.1038/s41419-022-05008-z |
| spellingShingle | Xing Liu Hongyan Deng Jinhua Tang Zixuan Wang Chunchun Zhu Xiaolian Cai Fangjing Rong Xiaoyun Chen Xueyi Sun Shuke Jia Gang Ouyang Wenhua Li Wuhan Xiao OTUB1 augments hypoxia signaling via its non-canonical ubiquitination inhibition of HIF-1α during hypoxia adaptation Cell Death and Disease |
| title | OTUB1 augments hypoxia signaling via its non-canonical ubiquitination inhibition of HIF-1α during hypoxia adaptation |
| title_full | OTUB1 augments hypoxia signaling via its non-canonical ubiquitination inhibition of HIF-1α during hypoxia adaptation |
| title_fullStr | OTUB1 augments hypoxia signaling via its non-canonical ubiquitination inhibition of HIF-1α during hypoxia adaptation |
| title_full_unstemmed | OTUB1 augments hypoxia signaling via its non-canonical ubiquitination inhibition of HIF-1α during hypoxia adaptation |
| title_short | OTUB1 augments hypoxia signaling via its non-canonical ubiquitination inhibition of HIF-1α during hypoxia adaptation |
| title_sort | otub1 augments hypoxia signaling via its non canonical ubiquitination inhibition of hif 1α during hypoxia adaptation |
| url | https://doi.org/10.1038/s41419-022-05008-z |
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