Ubiquitin precursor with C-terminal extension promotes proteostasis and longevity
Ubiquitin is a conserved modifier regulating the stability and function of numerous target proteins. In all eukaryotes, polyubiquitin precursors are generated and processed into ubiquitin monomers. The final ubiquitin unit always contains a C-terminal extension, but its physiological significance is unknown. Here, we show that C-terminally extended ubiquitin, termed CxUb, is essential for stress resistance, mitophagy, and longevity in Saccharomyces cerevisiae and Caenorhabditis elegans. CxUb forms ubiquitin chains and binds to a previously undescribed region within the ubiquitin chain-elongating E4 enzyme Ufd2, which also functions during stress and aging. Ufd2 recognizes CxUb and conjugates it to substrate proteins, triggering their degradation. By contrast, CxUb is not required for basal housekeeping functions of the ubiquitin-proteasome system. These data suggest that the CxUb encodes a functionally unique ubiquitin form, specialized for proteostasis defects, expanding the code of post-translational modification processes.
Authors
- Vincent Anton (ORCID: https://orcid.org/0000-0003-3008-6346)
- Natascia Ventura (ORCID: https://orcid.org/0000-0001-8718-4321)
- Reinhard Büttner (ORCID: https://orcid.org/0000-0001-8806-4786)
- Andreas S. Reichert (ORCID: https://orcid.org/0000-0001-9340-3113)
- Marcus Krüger (ORCID: https://orcid.org/0000-0002-5846-6941)
- Hendrik Nolte (ORCID: https://orcid.org/0000-0003-1560-5099)
- Selver Altin
- Dennis Domke
- Christina Behrendt
- Marcel Zimmermann (ORCID: https://orcid.org/0000-0001-7871-4052)
- Nahal Brocke‐Ahmadinejad (ORCID: https://orcid.org/0000-0002-7335-6564)
- Tânia Simões (ORCID: https://orcid.org/0000-0002-5971-4935)
- Katja Bendrin
- Thomas Hermanns
- R. Jürgen Dohmen (ORCID: https://orcid.org/0000-0002-5756-6780)
- Mafalda Escobar‐Henriques (ORCID: https://orcid.org/0000-0002-0879-3119)
- Thorsten Hoppe (ORCID: https://orcid.org/0000-0002-4734-9352)
- Kai Mayor Völtzke
- Rajesh Kumar (ORCID: https://orcid.org/0000-0001-9346-8806)
- Kay Hofmann (ORCID: https://orcid.org/0000-0002-2289-9083)
Institutions
- University of Cologne (DE)
- Düsseldorf University Hospital (DE)
- Leibniz Institute of Environmental Medicine (DE)
- Cologne Excellence Cluster on Cellular Stress Responses in Aging Associated Diseases (DE)
- University Hospital Cologne (DE)
- Heinrich Heine University Düsseldorf (DE)
Publication Details
- Journal
- Molecular Cell
- Published
- 2025-09-24
- DOI
- https://doi.org/10.1016/j.molcel.2025.08.032
- Citations
- 2
- Primary Topic
- Ubiquitin and proteasome pathways
- Type
- article
- Field-Weighted Citation Impact
- 1.61