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A non-canonical function of RNF8 opposes TRAF6-mediated stabilization of HIF1α.
RSC Chemical Biology, DOI: 10.1039/d5cb00209e (2026)
Ubiquitination is a central regulatory mechanism controlling protein stability and signaling in eukaryotic cells. The precise control of this machinery is crucial to avoid the development of diseases. Here, we identify a previously unrecognized interaction between the E3 ligase RNF8 and HIF1α, the oxygen-sensitive subunit of the hypoxia-inducible transcription factor HIF1. RNF8 antagonizes TRAF6-mediated stabilization of HIF1α under hypoxic conditions. Importantly, this regulatory effect is independent of the RNF8 E3 ligase activity but requires its forkhead-associated (FHA) domain. Yeast two-hybrid assays reveal an interaction between RNF8 FHA domain and the C-terminal transactivation domain (TAD) of HIF1α, despite the absence of a canonical FHA-binding motif in HIF1α. This interaction is maintained in a hydroxylation-deficient HIF1α mutant, indicating that prolyl hydroxylation is not required. Our findings suggest a non-canonical mode of FHA-dependent association by which RNF8 modulates HIF1α stability and downstream transcriptional control, with potential implications for hypoxia-driven signaling in triple-negative breast cancer.
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Publication type
Article: Journal article
Document type
Scientific Article
Keywords
Ubiquitin Ligase Rnf8; Fha Domain; Activation; Degradation
ISSN (print) / ISBN
2633-0679
Journal
RSC Chemical Biology
Publisher
Royal Society of Chemistry (RSC)
Publishing Place
Thomas Graham House, Science Park, Milton Rd, Cambridge Cb4 0wf, Cambs, England
Institute(s)
Research Unit Signaling and Translation (SAT)
Grants
Deutsche Forschungsgemeinschaft