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Advancing the Exploration of the Ubiquitin-like Protein FUBI with Synthetic Chemical Tools

Francesca D'Amico1, Cami M P Talavera Ormeño1, Shivanganie Poeran1

  • 1Department of Cell and Chemical Biology, Leiden University Medical Center (LUMC), Einthovenweg 20, 2333 ZC, Leiden, The Netherlands.

Chembiochem : a European Journal of Chemical Biology
|June 4, 2025
PubMed

Insights

Researchers developed novel chemical tools to study the Ubiquitin-like protein FUBI (FUBI). These tools revealed new interactions and showed FUBI can inhibit UCHL3 activity, offering insights into cancer progression.

Area of Science:

  • Biochemistry
  • Chemical Biology
  • Molecular Oncology

Background:

  • The Ubiquitin-like protein FUBI, encoded by the FAU gene, is downregulated in several cancers, correlating with poor prognosis.
  • The precise regulatory mechanisms of FUBI in disease progression are not well understood.

Purpose of the Study:

  • To develop a synthetic platform for generating FUBI chemical tools.
  • To investigate FUBI conjugation and deconjugation enzymes and identify novel FUBI interactors.

Main Methods:

  • A linear synthetic platform was established for site-specific incorporation of unnatural building blocks, fluorophores, tags, and reactive warheads into FUBI.
  • Activity-based probes were synthesized and validated in cell lysate assays and proteomics.
  • A triazole-linked Di-FUBI was created to study FUBI chain modulators.

Main Results:

  • The synthetic platform successfully generated FUBI chemical tools.
  • Proteomics identified IMPDH1 and the deubiquitinase UCHL3 as novel Di-FUBI specific interactors.
  • Di-FUBI was found to inhibit UCHL3 cleavage activity in a concentration-dependent manner.

Conclusions:

  • The developed synthetic FUBI platform is versatile for creating chemical biology tools.
  • Novel interactions and regulatory roles of FUBI, including inhibition of UCHL3, were uncovered.
  • These findings advance the understanding of ubiquitin-like signaling in cancer.
Keywords:
FUBIUb‐like proteinsactivity‐based probeschemical biologypost‐translational modifications

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