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A non-canonical function of RNF8 opposes TRAF6-mediated stabilization of HIF1α.
RSC Chemical Biology 7, 1621–1631 (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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Publikationstyp
Artikel: Journalartikel
Dokumenttyp
Wissenschaftlicher Artikel
Schlagwörter
Ubiquitin Ligase Rnf8; Fha Domain; Activation; Degradation
ISSN (print) / ISBN
2633-0679
Zeitschrift
RSC Chemical Biology
Quellenangaben
Band: 7,
Heft: 8,
Seiten: 1621–1631
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