UBFD1

UBFD1 is a polyubiquitin-binding protein that links coenzyme A metabolism to the regulation of hypoxia-inducible factor stability (PMID:19285159). It was first identified as a novel polyubiquitin binder in protein array screening (PMID:19285159). UBFD1 binds coenzyme A through its PH domain, which itself undergoes CoAlation, and in a CoA-dependent manner scaffolds HIF-1α for proteasomal degradation. Disruption of CoA homeostasis through CoAsy deficiency abrogates the UBFD1–HIFα–proteasome association, stabilizing both HIF-1α and HIF-2α independently of the canonical oxygen-sensing pathway. Beyond these findings, no further mechanistic detail has been characterized in the available corpus.

1. 2009 Medium

   Established UBFD1 as a previously uncharacterized protein with the capacity to engage the ubiquitin system, framing it as a candidate adaptor in ubiquitin-dependent processes.

   Evidence Protein array screening with polyubiquitin as bait alongside known polyubiquitin binders as controls

   PMID:19285159

   Open questions at the time

   • Single binding-assay method without cellular validation of the interaction
   • No linkage assigned for the polyubiquitin chains bound
   • No physiological substrate or pathway identified
2. 2025 Medium

   Connected UBFD1 to CoA metabolism and HIF regulation, showing it scaffolds HIFα for proteasomal degradation in a CoA-dependent manner and defining a non-canonical, oxygen-independent route to HIF stabilization.

   Evidence Proximity-labelling proteomics, CoAsy loss-of-function, PH-domain mutagenesis, and CoAlation assays (preprint)

   Open questions at the time

   • Not yet peer-reviewed
   • Mechanism connecting polyubiquitin binding (2009) to the CoA/HIF scaffolding role is not resolved
   • Structural basis of CoA binding and CoAlation of the PH domain not defined

• How UBFD1's polyubiquitin-binding activity mechanistically integrates with its CoA-dependent HIFα scaffolding function, and whether it acts more broadly in ubiquitin-dependent degradation, remains unresolved.
• No reconciliation of the ubiquitin-binding and CoA-binding activities
• No structural model of UBFD1 or its complexes
• No additional substrates or interactors validated