Filament formation and NAD processing by noncanonical human FAM118 sirtuins

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.