Stimulating and suppressing HIFs

Cells respond and adapt to hypoxia (low oxygen) in part by activating the α subunits of the HIF family of transcription factors. Daly et al. performed proteomics analysis of transfected cells to explore the protein modifications and binding partners for full-length versions of the hypoxia-response subunits HIF-1α and HIF-2α. Their findings, which included a phosphorylated cysteine, protein stability effects, and interactions with mitochondrial proteins, indicate that the oxygen-dependent regulation of HIF activity is more extensive and complex than was previously appreciated. This dataset will help to delineate the selective regulation and signaling mechanisms of these closely related isoforms in fine-tuning the cellular response to hypoxia.


Cellular adaptation to low-oxygen environments is mediated in part by the hypoxia-inducible factors (HIFs). Like other transcription factors, the stability and transcriptional activity of HIFs—and consequently, the hypoxic response—are regulated by post-translational modifications (PTMs) and changes in protein-protein interactions. Our current understanding of PTM-mediated regulation of HIFs is primarily based on in vitro protein fragment–based studies typically validated in fragment-expressing cells treated with hypoxia-mimicking compounds. Here, we used immunoprecipitation-based mass spectrometry to characterize the PTMs and binding partners for full-length HIF-1α and HIF-2α under normoxic (21% oxygen) and hypoxic (1% oxygen) conditions. Hypoxia substantially altered the complexity and composition of the HIFα protein interaction networks, particularly for HIF-2α, with the hypoxic networks of both isoforms being enriched for mitochondrial proteins. Moreover, both HIFα isoforms were heavily covalently modified. We identified ~40 PTM sites composed of 13 different types of modification on both HIFα isoforms, including multiple cysteine modifications and an unusual phosphocysteine. More than 80% of the PTMs identified were not previously known and about half exhibited oxygen dependency. We further characterized an evolutionarily conserved phosphorylation of Ser31 in HIF-1α as a regulator of its transcriptional function, and we propose functional roles for Thr406, Thr528, and Ser581 in HIF-2α. These data will help to delineate the different physiological roles of these closely related isoforms in fine-tuning the hypoxic response.

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Supplementary Material


Figs. S1 to S6
Tables S1 to S9
Data files S1 and S2


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Science Signaling
Volume 14 | Issue 692
July 2021

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Received: 12 November 2020
Accepted: 24 May 2021


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We thank the technical support received for confocal imaging by the Centre for Cell Imaging staff, especially J. Adcott for support and assistance in this work. Funding: This work was supported by the Biotechnology and Biological Sciences Research Council (BBSRC; BB/R000182/1 and BB/M012557/1 to C.E.E.). L.A.D. was supported by a BBSRC DTP Ph.D. studentship award. Equipment for imaging was funded by the Medical Research Council (MRCMR/K015931/1). Author contributions: L.A.D., V.S., and C.E.E. designed the project; L.A.D. performed most of the experiments, with P.J.B. contributing to MS data acquisition; M.B. performed the ChIP-seq experiments with input from S.R.; L.A.D. and C.E.E. analyzed the proteomics/MS data; L.A.D., V.S., and C.E.E. wrote the manuscript with contribution from all authors. All authors have given approval to the final version of the manuscript. Competing interests: The authors declare that they have no competing interests. Data and materials availability: The MS proteomics data have been deposited to the ProteomeXchange Consortium via the PRIDE partner repository with the dataset identifier PXD022479. Generated plasmids are available from Addgene. All other data needed to evaluate the conclusions in the paper are present in the paper or the Supplementary Materials.



Department of Biochemistry and System Biology, Institute of Systems, Molecular, and Integrative Biology, University of Liverpool, Liverpool L69 7ZB, UK.
Centre for Proteome Research, University of Liverpool, Liverpool L69 7ZB, UK.
Centre for Proteome Research, University of Liverpool, Liverpool L69 7ZB, UK.
Department of Molecular Physiology and Cell Signaling, Institute of Systems, Molecular, and Integrative Biology, University of Liverpool, Liverpool L69 7ZB, UK.
Department of Molecular Physiology and Cell Signaling, Institute of Systems, Molecular, and Integrative Biology, University of Liverpool, Liverpool L69 7ZB, UK.
Department of Molecular Physiology and Cell Signaling, Institute of Systems, Molecular, and Integrative Biology, University of Liverpool, Liverpool L69 7ZB, UK.
Centre for Cell Imaging, University of Liverpool, Liverpool L69 7ZB, UK.
Department of Biochemistry and System Biology, Institute of Systems, Molecular, and Integrative Biology, University of Liverpool, Liverpool L69 7ZB, UK.
Centre for Proteome Research, University of Liverpool, Liverpool L69 7ZB, UK.

Funding Information

Medical Research Council: MRCMR/K015931/1


Corresponding author. Email: [email protected] (C.E.E.); [email protected] (V.S.)

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