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<p>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.</p>

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Filament formation and NAD processing by noncanonical human FAM118 sirtuins

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2025年11月17日

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  • 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

摘要

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.