2. Academic Validation
  3. BioE3 identifies specific substrates of ubiquitin E3 ligases

BioE3 identifies specific substrates of ubiquitin E3 ligases

  • Nat Commun. 2023 Nov 23;14(1):7656. doi: 10.1038/s41467-023-43326-8.
Orhi Barroso-Gomila # 1,  Laura Merino-Cacho # 1,  Veronica Muratore 1,  Coralia Perez 1,  Vincenzo Taibi 2,  Elena Maspero 2,  Mikel Azkargorta 1 3,  Ibon Iloro 1 3,  Fredrik Trulsson 4,  Alfred C O Vertegaal 4,  Ugo Mayor 5 6,  Felix Elortza 1 3,  Simona Polo 2 7,  Rosa Barrio 8,  James D Sutherland 9
Affiliations

Affiliations

  • 1 Center for Cooperative Research in Biosciences (CIC bioGUNE), Basque Research and Technology Alliance (BRTA), Bizkaia Technology Park, Building 801A, 48160, Derio, Spain.
  • 2 IFOM ETS, The AIRC Institute of Molecular Oncology, Milan, Italy.
  • 3 CIBERehd, Instituto de Salud Carlos III, C/ Monforte de Lemos 3-5, Pabellón 11, Planta 0, 28029, Madrid, Spain.
  • 4 Cell and Chemical Biology, Leiden University Medical Center (LUMC), 2333, ZA, Leiden, The Netherlands.
  • 5 Ikerbasque, Basque Foundation for Science, 48011, Bilbao, Spain.
  • 6 Biochemistry and Molecular Biology Department, University of the Basque Country (UPV/EHU), E-48940, Leioa, Spain.
  • 7 Dipartimento di oncologia ed emato-oncologia, Università degli Studi di Milano, Milan, Italy.
  • 8 Center for Cooperative Research in Biosciences (CIC bioGUNE), Basque Research and Technology Alliance (BRTA), Bizkaia Technology Park, Building 801A, 48160, Derio, Spain. rbarrio@cicbiogune.es.
  • 9 Center for Cooperative Research in Biosciences (CIC bioGUNE), Basque Research and Technology Alliance (BRTA), Bizkaia Technology Park, Building 801A, 48160, Derio, Spain. jsutherland@cicbiogune.es.
  • # Contributed equally.
PMID: 37996419 DOI: 10.1038/s41467-023-43326-8
Abstract

Hundreds of E3 Ligases play a critical role in recognizing specific substrates for modification by ubiquitin (Ub). Separating genuine targets of E3s from E3-interactors remains a challenge. We present BioE3, a powerful approach for matching substrates to Ub E3 Ligases of interest. Using BirA-E3 ligase fusions and bioUb, site-specific biotinylation of Ub-modified substrates of particular E3s facilitates proteomic identification. We show that BioE3 identifies both known and new targets of two RING-type E3 ligases: RNF4 (DNA damage response, PML bodies), and MIB1 (endocytosis, Autophagy, centrosome dynamics). Versatile BioE3 identifies targets of an organelle-specific E3 (MARCH5) and a relatively uncharacterized E3 (RNF214). Furthermore, BioE3 works with NEDD4, a HECT-type E3, identifying new targets linked to vesicular trafficking. BioE3 detects altered specificity in response to chemicals, opening avenues for targeted protein degradation, and may be applicable for other Ub-likes (UbLs, e.g., SUMO) and E3 types. BioE3 applications shed LIGHT on cellular regulation by the complex UbL network.

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