Filament formation and NAD processing by noncanonical human FAM118 sirtuins

Domagoj Baretić; Sophia Missoury; Karishma Patel; Maximilien Martinez; Franck Coste; Kang Zhu; Rebecca Smith; Anna Georgina Kopasz; Yang Lu; Nicolas Bigot; Catherine Chapuis; Romane Riou; Nina Đukić; Stéphane Goffinont; Valentin Pressoir; Sara Patačko; Gyula Timinszky; Marc Delarue; Bertrand Castaing; Dragana Ahel; Andreja Mikoč; Sébastien Huet; Ivan Ahel; Marcin J. Suskiewicz

doi:10.1038/s41594-025-01715-1

Filament formation and NAD processing by noncanonical human FAM118 sirtuins

Domagoj Baretić, Sophia Missoury, Karishma Patel, Maximilien Martinez, Franck Coste, Kang Zhu, Rebecca Smith, Anna Georgina Kopasz, Yang Lu, Nicolas Bigot, Catherine Chapuis, Romane Riou, Nina Đukić, Stéphane Goffinont, Valentin Pressoir, Sara Patačko, Gyula Timinszky, Marc Delarue, Bertrand Castaing, Dragana AhelAndreja Mikoč, Sébastien Huet^*, Ivan Ahel^*, Marcin J. Suskiewicz^*

^*Corresponding author for this work

Research output: Contribution to journal › Article › peer-review

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.

Original language	English
Journal	Nature Structural and Molecular Biology
DOIs	https://doi.org/10.1038/s41594-025-01715-1
State	Accepted/In press - 2025
Externally published	Yes

Access to Document

10.1038/s41594-025-01715-1

Cite this

Baretić, D., Missoury, S., Patel, K., Martinez, M., Coste, F., Zhu, K., Smith, R., Kopasz, A. G., Lu, Y., Bigot, N., Chapuis, C., Riou, R., Đukić, N., Goffinont, S., Pressoir, V., Patačko, S., Timinszky, G., Delarue, M., Castaing, B., ... Suskiewicz, M. J. (Accepted/In press). Filament formation and NAD processing by noncanonical human FAM118 sirtuins. Nature Structural and Molecular Biology. https://doi.org/10.1038/s41594-025-01715-1

@article{93f1496890434c5fb1be441cd817db99,

title = "Filament formation and NAD processing by noncanonical human FAM118 sirtuins",

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.",

author = "Domagoj Bareti{\'c} and Sophia Missoury and Karishma Patel and Maximilien Martinez and Franck Coste and Kang Zhu and Rebecca Smith and Kopasz, \{Anna Georgina\} and Yang Lu and Nicolas Bigot and Catherine Chapuis and Romane Riou and Nina {\D}uki{\'c} and St{\'e}phane Goffinont and Valentin Pressoir and Sara Pata{\v c}ko and Gyula Timinszky and Marc Delarue and Bertrand Castaing and Dragana Ahel and Andreja Miko{\v c} and S{\'e}bastien Huet and Ivan Ahel and Suskiewicz, \{Marcin J.\}",

note = "Publisher Copyright: {\textcopyright} The Author(s) 2025.",

year = "2025",

doi = "10.1038/s41594-025-01715-1",

language = "英语",

journal = "Nature Structural and Molecular Biology",

issn = "1545-9993",

publisher = "Nature Research",

}

Baretić, D, Missoury, S, Patel, K, Martinez, M, Coste, F, Zhu, K, Smith, R, Kopasz, AG, Lu, Y, Bigot, N, Chapuis, C, Riou, R, Đukić, N, Goffinont, S, Pressoir, V, Patačko, S, Timinszky, G, Delarue, M, Castaing, B, Ahel, D, Mikoč, A, Huet, S, Ahel, I & Suskiewicz, MJ 2025, 'Filament formation and NAD processing by noncanonical human FAM118 sirtuins', Nature Structural and Molecular Biology. https://doi.org/10.1038/s41594-025-01715-1

TY - JOUR

T1 - Filament formation and NAD processing by noncanonical human FAM118 sirtuins

AU - Baretić, Domagoj

AU - Missoury, Sophia

AU - Patel, Karishma

AU - Martinez, Maximilien

AU - Coste, Franck

AU - Zhu, Kang

AU - Smith, Rebecca

AU - Kopasz, Anna Georgina

AU - Lu, Yang

AU - Bigot, Nicolas

AU - Chapuis, Catherine

AU - Riou, Romane

AU - Đukić, Nina

AU - Goffinont, Stéphane

AU - Pressoir, Valentin

AU - Patačko, Sara

AU - Timinszky, Gyula

AU - Delarue, Marc

AU - Castaing, Bertrand

AU - Ahel, Dragana

AU - Mikoč, Andreja

AU - Huet, Sébastien

AU - Ahel, Ivan

AU - Suskiewicz, Marcin J.

PY - 2025

Y1 - 2025

N2 - 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.

AB - 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.

UR - https://www.scopus.com/pages/publications/105022064038

U2 - 10.1038/s41594-025-01715-1

DO - 10.1038/s41594-025-01715-1

M3 - 文章

AN - SCOPUS:105022064038

SN - 1545-9993

JO - Nature Structural and Molecular Biology

JF - Nature Structural and Molecular Biology

ER -

Filament formation and NAD processing by noncanonical human FAM118 sirtuins

Abstract

Access to Document

Other files and links

Fingerprint

Cite this