An oxygen-insensitive Hif-3α isoform inhibits Wnt signaling by destabilizing the nuclear β-catenin complex
Hypoxia-inducible factors (HIFs), while best known for their roles in the hypoxic response, have oxygen-independent roles in early development with poorly defined mechanisms. Here, we report a novel Hif-3α variant, Hif-3α2, in zebrafish. Hif-3α2 lacks the bHLH, PAS, PAC, and ODD domains, and is expr...
| Main Authors: | , , , , |
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| Format: | Article |
| Language: | English |
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eLife Sciences Publications Ltd
2016-01-01
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| Series: | eLife |
| Subjects: | |
| Online Access: | https://elifesciences.org/articles/08996 |
| _version_ | 1818019644543336448 |
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| author | Peng Zhang Yan Bai Ling Lu Yun Li Cunming Duan |
| author_facet | Peng Zhang Yan Bai Ling Lu Yun Li Cunming Duan |
| author_sort | Peng Zhang |
| collection | DOAJ |
| description | Hypoxia-inducible factors (HIFs), while best known for their roles in the hypoxic response, have oxygen-independent roles in early development with poorly defined mechanisms. Here, we report a novel Hif-3α variant, Hif-3α2, in zebrafish. Hif-3α2 lacks the bHLH, PAS, PAC, and ODD domains, and is expressed in embryonic and adult tissues independently of oxygen availability. Hif-3α2 is a nuclear protein with significant hypoxia response element (HRE)-dependent transcriptional activity. Hif-3α2 overexpression not only decreases embryonic growth and developmental timing but also causes left-right asymmetry defects. Genetic deletion of Hif-3α2 by CRISPR/Cas9 genome editing increases, while Hif-3α2 overexpression decreases, Wnt/β-catenin signaling. This action is independent of its HRE-dependent transcriptional activity. Mechanistically, Hif-3α2 binds to β-catenin and destabilizes the nuclear β-catenin complex. This mechanism is distinct from GSK3β-mediated β-catenin degradation and is conserved in humans. These findings provide new insights into the oxygen-independent actions of HIFs and uncover a novel mechanism regulating Wnt/β-catenin signaling. |
| first_indexed | 2024-04-14T07:53:56Z |
| format | Article |
| id | doaj.art-8f981868d3114979a309b4b7f623e13f |
| institution | Directory Open Access Journal |
| issn | 2050-084X |
| language | English |
| last_indexed | 2024-04-14T07:53:56Z |
| publishDate | 2016-01-01 |
| publisher | eLife Sciences Publications Ltd |
| record_format | Article |
| series | eLife |
| spelling | doaj.art-8f981868d3114979a309b4b7f623e13f2022-12-22T02:05:06ZengeLife Sciences Publications LtdeLife2050-084X2016-01-01510.7554/eLife.08996An oxygen-insensitive Hif-3α isoform inhibits Wnt signaling by destabilizing the nuclear β-catenin complexPeng Zhang0Yan Bai1Ling Lu2Yun Li3Cunming Duan4https://orcid.org/0000-0001-6794-2762Department of Molecular, Cellular, and Developmental Biology, University of Michigan, Ann Arbor, United StatesDepartment of Molecular, Cellular, and Developmental Biology, University of Michigan, Ann Arbor, United StatesKey Laboratory of Marine Drugs, Ministry of Education and School of Medicine and Pharmacy, Ocean University of China, Qingdao, ChinaKey Laboratory of Marine Drugs, Ministry of Education and School of Medicine and Pharmacy, Ocean University of China, Qingdao, ChinaDepartment of Molecular, Cellular, and Developmental Biology, University of Michigan, Ann Arbor, United StatesHypoxia-inducible factors (HIFs), while best known for their roles in the hypoxic response, have oxygen-independent roles in early development with poorly defined mechanisms. Here, we report a novel Hif-3α variant, Hif-3α2, in zebrafish. Hif-3α2 lacks the bHLH, PAS, PAC, and ODD domains, and is expressed in embryonic and adult tissues independently of oxygen availability. Hif-3α2 is a nuclear protein with significant hypoxia response element (HRE)-dependent transcriptional activity. Hif-3α2 overexpression not only decreases embryonic growth and developmental timing but also causes left-right asymmetry defects. Genetic deletion of Hif-3α2 by CRISPR/Cas9 genome editing increases, while Hif-3α2 overexpression decreases, Wnt/β-catenin signaling. This action is independent of its HRE-dependent transcriptional activity. Mechanistically, Hif-3α2 binds to β-catenin and destabilizes the nuclear β-catenin complex. This mechanism is distinct from GSK3β-mediated β-catenin degradation and is conserved in humans. These findings provide new insights into the oxygen-independent actions of HIFs and uncover a novel mechanism regulating Wnt/β-catenin signaling.https://elifesciences.org/articles/08996hypoxiawnt signalingzebrafish |
| spellingShingle | Peng Zhang Yan Bai Ling Lu Yun Li Cunming Duan An oxygen-insensitive Hif-3α isoform inhibits Wnt signaling by destabilizing the nuclear β-catenin complex eLife hypoxia wnt signaling zebrafish |
| title | An oxygen-insensitive Hif-3α isoform inhibits Wnt signaling by destabilizing the nuclear β-catenin complex |
| title_full | An oxygen-insensitive Hif-3α isoform inhibits Wnt signaling by destabilizing the nuclear β-catenin complex |
| title_fullStr | An oxygen-insensitive Hif-3α isoform inhibits Wnt signaling by destabilizing the nuclear β-catenin complex |
| title_full_unstemmed | An oxygen-insensitive Hif-3α isoform inhibits Wnt signaling by destabilizing the nuclear β-catenin complex |
| title_short | An oxygen-insensitive Hif-3α isoform inhibits Wnt signaling by destabilizing the nuclear β-catenin complex |
| title_sort | oxygen insensitive hif 3α isoform inhibits wnt signaling by destabilizing the nuclear β catenin complex |
| topic | hypoxia wnt signaling zebrafish |
| url | https://elifesciences.org/articles/08996 |
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