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Ringelstetter, L. ; Mersdorf-Weber, E. ; Schorpp, K.K. ; Hadian, K.

A non-canonical function of RNF8 opposes TRAF6-mediated stabilization of HIF1α.

RSC Chemical Biology, DOI: 10.1039/d5cb00209e (2026)
Verlagsversion Forschungsdaten DOI
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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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Publikationstyp Artikel: Journalartikel
Dokumenttyp Wissenschaftlicher Artikel
Schlagwörter Ubiquitin Ligase Rnf8; Fha Domain; Activation; Degradation
ISSN (print) / ISBN 2633-0679
Zeitschrift RSC Chemical Biology
Verlag Royal Society of Chemistry (RSC)
Verlagsort Thomas Graham House, Science Park, Milton Rd, Cambridge Cb4 0wf, Cambs, England
Institut(e) Research Unit Signaling and Translation (SAT)
Förderungen Deutsche Forschungsgemeinschaft