Baretić, Domagoj and Missoury, Sophia and Patel, Karishma and Martinez, Maximilien and Coste, Franck and Zhu, Kang and Smith, Rebecca and Kopasz, Anna Georgina and Lu, Yang and Bigot, Nicolas and Chapuis, Catherine and Riou, Romane and Đukić, Nina and Goffinont, Stéphane and Pressoir, Valentin and Patačko, Sara and Timinszky, Gyula and Delarue, Marc and Castaing, Bertrand and Ahel, Dragana and Mikoč, Andreja and Huet, Sébastien and Ahel, Ivan and Suskiewicz, Marcin J. (2025) Filament formation and NAD processing by noncanonical human FAM118 sirtuins. NATURE STRUCTURAL & MOLECULAR BIOLOGY, 32 (12). pp. 2526-2541. ISSN 1545-9993
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Abstract
Sirtuins are an ancient family of enzymes with diverse nicotinamide adenine dinucleotide (NAD)-dependent activities. Here we identify family with sequence similarity 118 member B (FAM118B) and FAM118A—two understudied vertebrate proteins—as vertebrate-specific sirtuins with similarities to bacterial antiphage sirtuins. We show that human FAM118B forms head-to-tail filaments both in vitro and in living human cells, a feature that appears to be conserved in both FAM118B and its paralog FAM118A across vertebrates. While human FAM118B and FAM118A have individually very weak NAD-processing activity in vitro, their interaction leads to markedly increased activity, suggesting a tightly regulated system. The overexpression of wild-type human FAM118B and FAM118A leads to strongly decreased NAD levels in human cells, an effect that is abolished in catalytically dead or filament-deficient mutants. Our study highlights filament formation and NAD processing as conserved mechanisms among immunity-associated sirtuins across evolution.
| Item Type: | Article |
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| Additional Information: | Funding Agency and Grant Number: French National Research Agency [ANR-10-INBS-04]; European Union [101078837]; Centre National de la Recherche Scientifique; Biotechnology and Biological Sciences Research Council [BB/R007195/1, BB/W016613/1]; Wellcome Trust [210634, 223107, 302632]; CRUK [C35050/A22284]; European Molecular Biology Organization postdoctoral fellowship [ALTF 733-2024]; Agence Nationale de la Recherche [ANR-23-CE12-0025, ANR-24-CE42-4982] Funding text: We thank A. Mishra for comments. We thank R. Matadeen for help with data collection of full-length FAM118B on a Titan Krios, F. Moreira-Leite for help with sample vitrification and E. Lowe and B. Rozman for maintenance of the cluster used for data computing at the cryoEM facility COSMIC (University of Oxford). We thank A. Wainman and the Dunn School Bioimaging Facility for expert advice and access to the microscope. We thank the Microscopy-Rennes Imaging Center (BIOSIT, Universite Rennes), a member of France BioImaging supported by the French National Research Agency (grant no. ANR-10-INBS-04), for access to optical microscopy and S. Dutertre, X. Pinson and G. Le Marchand for their assistance on the microscopes. We thank the staff of the NanoImaging Core Facility at Institut Pasteur for access to Glacios microscope for collecting an initial FAM118B24-334 cryoEM dataset. We acknowledge H. S. Kwong and the CM01 beamline at ESRF Grenoble for access to the Titan Krios and assistance with FAM118B24-334 data acquisition. M.J.S. is supported by the European Union's Horizon Europe research and innovation program (ERC starting grant 'SUMOwriteNread', no. 101078837) and the Centre National de la Recherche Scientifique and is an associated fellow of Le Studium Loire Valley Institute of Advanced Studies and the ATIP-Avenir program. The work in I.A.'s lab was supported by the following grants: Biotechnology and Biological Sciences Research Council (BB/R007195/1 and BB/W016613/1), Wellcome Trust (210634, 223107, and 302632) and CRUK (C35050/A22284). K.P. is supported by a European Molecular Biology Organization postdoctoral fellowship (ALTF 733-2024). The work in S.H.'s lab was supported by grants from the Agence Nationale de la Recherche (ANR-23-CE12-0025, OxiREPTRA and ANR-24-CE42-4982, Eve-SMLM). |
| Subjects: | Q Science / természettudomány > QH Natural history / természetrajz > QH301 Biology / biológia > QH3015 Molecular biology / molekuláris biológia |
| SWORD Depositor: | MTMT SWORD |
| Depositing User: | MTMT SWORD |
| Date Deposited: | 08 Feb 2026 09:20 |
| Last Modified: | 08 Feb 2026 09:20 |
| URI: | https://real.mtak.hu/id/eprint/233507 |
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