Molecular mechanism of CtBP1-S/BARS–driven membrane fission and its cellular control by metabolic ligands
CtBP1-S/BARS (C-terminal binding protein 1-S/Brefeldin A ADP-Ribosylation Substrate) is a moonlighting protein with key roles in membrane trafficking and gene regulation. We show that CtBP1-S/BARS couples enzymatic lipid remodeling [lysophosphatidic acid (LPA)-to-phosphatidic acid (PA) conversion] with membrane deformation to drive fission and that this activity is directly controlled by metabolic ligands. CtBP1-S/BARS exists as a monomer or dimer. The monomeric, acyl-CoA-bound form drives membrane fission by coupling acyltransferase-dependent LPA-to-PA conversion with amphipathic helix insertion into PA-enriched membranes. Under metabolic stress, reduced nicotinamide adenine dinucleotide (NADH) binding triggers dimerization and structural rearrangements that disable fission, enabling the binding of transcription factors regulating apoptosis and energy metabolism. This NADH/acyl-CoA competition likely coordinates trafficking shutdown with gene expression programs through a single conformational change. In intact cells, increased NADH promotes nuclear accumulation of dimeric/tetrameric CtBP1-S/BARS, whereas elevated acyl-CoA favors the cytosolic, membrane-associated monomer, indicating that cofactor availability determines protein function under physiological and stress conditions. This work reveals the structural basis for integrating membrane transport with transcriptional control, demonstrating how evolution embeds distinct cellular functions into a unified molecular pathway.
Authors
- Rosario Oliva (ORCID: https://orcid.org/0000-0003-1763-1768)
- E. Esposito (ORCID: https://orcid.org/0000-0002-5347-247X)
- Matteo Lo Monte (ORCID: https://orcid.org/0000-0002-6279-2942)
- Carmen Valente (ORCID: https://orcid.org/0000-0002-6244-9108)
- Mathias Ziegler (ORCID: https://orcid.org/0000-0001-6961-2396)
- Alberto Luini (ORCID: https://orcid.org/0000-0002-8729-2549)
- Daniela Corda (ORCID: https://orcid.org/0000-0002-3614-751X)
- Jesús Sot (ORCID: https://orcid.org/0000-0001-9508-6596)
- Juha P. Kallio (ORCID: https://orcid.org/0000-0003-3092-4012)
- Gennaro Sanità (ORCID: https://orcid.org/0000-0002-8943-6980)
- Angela Filograna (ORCID: https://orcid.org/0000-0002-0175-0415)
- Pompea Del Vecchio (ORCID: https://orcid.org/0000-0002-9760-3478)
- Alicia Alonso (ORCID: https://orcid.org/0000-0002-2730-7470)
- Pietro Lupetti (ORCID: https://orcid.org/0000-0003-4316-9861)
- Stefano De Tito (ORCID: https://orcid.org/0000-0002-9493-9371)
- Daniela Spano (ORCID: https://orcid.org/0000-0003-3567-6492)
- Gabriele Turacchio (ORCID: https://orcid.org/0000-0002-0959-3266)
- Mikhail A. Zhukovsky
- Félix M. Goñi (ORCID: https://orcid.org/0000-0001-6270-9216)
- Michael M. Kozlov
- Nina Dathan (ORCID: https://orcid.org/0000-0001-5791-5357)
Institutions
- University of Siena (IT)
- Tel Aviv University (IL)
- University of the Basque Country (ES)
- Institute of Applied Science and Intelligent Systems (IT)
- Fundación Biofísica Bizkaia (ES)
- Institute for Experimental Endocrinology and Oncology (IT)
- Helix (United States) (US)
- University of Bergen (NO)
- Donostia International Physics Center (ES)
- University of Naples Federico II (IT)
Publication Details
- Journal
- Science Advances
- Published
- 2026-07-24
- DOI
- https://doi.org/10.1126/sciadv.aee0624
- Primary Topic
- Kruppel-like factors research
- Type
- article
- Field-Weighted Citation Impact
- 0.00
Funders
- Fondazione AIRC per la ricerca sul cancro ETS
- Eusko Jaurlaritza
- Ministero dell’Istruzione, dell’Università e della Ricerca
- Regione Campania
- Ministero dello Sviluppo Economico
- Ministero dell'Università e della Ricerca