Universität zu Köln

Altin, Selver, Simões, Tânia, Behrendt, Christina, Anton, Vincent, Domke, Dennis, Völtzke, Kai Mayor, Kumar, Rajesh, Nolte, Hendrik, Hermanns, Thomas, Brocke-Ahmadinejad, Nahal, Bendrin, Katja, Zimmermann, Marcel, Büttner, Reinhard, Ventura, Natascia, Krüger, Marcus, Dohmen, R. Jürgen, Hofmann, Kay, Hoppe, Thorsten, Reichert, Andreas S. and Escobar-Henriques, Mafalda ORCID: 0000-0002-0879-3119 (2025). Ubiquitin precursor with C-terminal extension promotes proteostasis and longevity. Molecular Cell, 85 (19). 3677-3693.e7. Elsevier. ISSN 1097-2765

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Abstract

Ubiquitin is a conserved modifier regulating the stability and function of numerous target proteins. In all eu- karyotes, 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 func- tions 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.

Item Type:	Article
Creators:	Creators Email ORCID ORCID Put Code Altin, Selver UNSPECIFIED UNSPECIFIED UNSPECIFIED Simões, Tânia UNSPECIFIED UNSPECIFIED UNSPECIFIED Behrendt, Christina UNSPECIFIED UNSPECIFIED UNSPECIFIED Anton, Vincent UNSPECIFIED UNSPECIFIED UNSPECIFIED Domke, Dennis UNSPECIFIED UNSPECIFIED UNSPECIFIED Völtzke, Kai Mayor UNSPECIFIED UNSPECIFIED UNSPECIFIED Kumar, Rajesh UNSPECIFIED UNSPECIFIED UNSPECIFIED Nolte, Hendrik UNSPECIFIED UNSPECIFIED UNSPECIFIED Hermanns, Thomas UNSPECIFIED UNSPECIFIED UNSPECIFIED Brocke-Ahmadinejad, Nahal UNSPECIFIED UNSPECIFIED UNSPECIFIED Bendrin, Katja UNSPECIFIED UNSPECIFIED UNSPECIFIED Zimmermann, Marcel UNSPECIFIED UNSPECIFIED UNSPECIFIED Büttner, Reinhard UNSPECIFIED UNSPECIFIED UNSPECIFIED Ventura, Natascia UNSPECIFIED UNSPECIFIED UNSPECIFIED Krüger, Marcus UNSPECIFIED UNSPECIFIED UNSPECIFIED Dohmen, R. Jürgen UNSPECIFIED UNSPECIFIED UNSPECIFIED Hofmann, Kay UNSPECIFIED UNSPECIFIED UNSPECIFIED Hoppe, Thorsten UNSPECIFIED UNSPECIFIED UNSPECIFIED Reichert, Andreas S. UNSPECIFIED UNSPECIFIED UNSPECIFIED Escobar-Henriques, Mafalda UNSPECIFIED https://orcid.org/0000-0002-0879-3119 UNSPECIFIED
URN:	urn:nbn:de:hbz:38-809829
Identification Number:	10.1016/j.molcel.2025.08.032
Journal or Publication Title:	Molecular Cell
Volume:	85
Number:	19
Page Range:	3677-3693.e7
Number of Pages:	25
Date:	October 2025
Publisher:	Elsevier
ISSN:	1097-2765
Language:	English
Faculty:	Faculty of Medicine
Divisions:	CECAD - Cluster of Excellence Cellular Stress Responses in Aging-Associated Diseases Faculty of Medicine > Humangenetik > Institut für Humangenetik Faculty of Medicine > Pathologie und Neuropathologie > Institut für Pathologie Zentrum für Molekulare Medizin
Subjects:	Medical sciences Medicine
Uncontrolled Keywords:	Keywords Language CxUb ; ubiquitin ; stress ; proteostasis ; mitochondria ; mitophagy ; aging ; E4 ; Ufd2 ; mitofusin English
['eprint_fieldname_oa_funders' not defined]:	Publikationsfonds UzK
Refereed:	Yes
URI:	http://kups.ub.uni-koeln.de/id/eprint/80982