The E3-ome gene-centric compendium reveals the human E3 ligase landscape.

20/03/2026

Cell

Authors: Ngee Kiat Chua, Tania J González-Robles, Cameron J Reddington, Jane Dudley-Fraser, Richard W Birkinshaw, Jiru Han, Ashleigh Solano, Soon Wei Wong, Tomasz Kochańczyk, Joshua J Peter, Mark A Nakasone, Florian Aust, Jacob Munro, Yeh Huei Tong, Julie Iskander, Waruni Abeysekera, Alex Garnham, Hannah Huckstep, Matthew E Ritchie, Ingrid Wertz, Sarah Hymowitz, Sharad Kumar, Ron C Conaway, Gilbert G Privé, Alex N Bullock, Jeffrey J Babon, Rachel E Klevit, Sonja Lorenz, Alessio Ciulli, Eric S Fischer, Nicolas H Thomä, Radosław P Nowak, Brenda A Schulman, Michael Rapé, Katrin Rittinger, Julia K Pagan, Melanie Bahlo, Joel P Mackay, Peter D Mace, Christopher D Lima, Ronald T Hay, David Komander, Bernhard C Lechtenberg, Claudio A P Joazeiro, Michele Pagano, Kay Hofmann, Rebecca Feltham

To define and systematically characterize the human E3 ubiquitin ligase (E3) landscape, we generated the E3-ome, a compendium of E3s encoded by the human genome. The E3-ome integrates experimental data, bioinformatics, and published research, revealing 672 high-confidence E3s. We standardized E3 classifications to create a unified framework for annotation and comparative analysis. The E3-ome identified several previously unrecognized domains, motifs, E3 candidates, and relationships, expanding the diversity of E3s. Furthermore, the E3-ome mapped the spatial and physiological organization of E3s across human tissues and cell types, revealing context-dependent E3s. Genetic analyses identified disease-associated variants across the E3-ome, linking E3s to diverse human pathologies. Together, these analyses define the human E3 landscape at high resolution and deliver a foundational resource to drive mechanistic and therapeutic discovery.

PMID: 41864206