Filament formation and NAD processing by noncanonical human FAM118 sirtuins

Baretić, Domagoj; Missoury, Sophia; Patel, Karishma; Martinez, Maximilien; Coste, Franck; Zhu, Kang; Smith, Rebecca; Kopasz, Anna Georgina; Lu, Yang; Bigot, Nicolas; Chapuis, Catherine; Riou, Romane; Đukić, Nina; Goffinont, Stéphane; Pressoir, Valentin; Patačko, Sara; Timinszky, Gyula; Delarue, Marc; Castaing, Bertrand; Ahel, Dragana; Mikoč, Andreja; Huet, Sébastien; Ahel, Ivan; 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
Uncontrolled Keywords:	ADP-ribozilacija; PTM
Subjects:	NATURAL SCIENCES > Biology
Divisions:	Division of Molecular Biology
Depositing User:	Ema Buhin Šaler
Date Deposited:	27 Feb 2026 10:03
URI:	http://fulir.irb.hr/id/eprint/11287
DOI:	10.1038/s41594-025-01715-1

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