Filament formation and NAD processing by noncanonical human FAM118 sirtuins

Area of Science:

• Biochemistry
• Molecular Biology
• Enzymology

Background:

• Sirtuins are ancient nicotinamide adenine dinucleotide (NAD)-dependent enzymes.
• FAM118B and FAM118A are understudied vertebrate proteins.
• Bacterial antiphage sirtuins are involved in immunity.

Purpose of the Study:

• Identify FAM118B and FAM118A as vertebrate-specific sirtuins.
• Investigate their biochemical activities and cellular functions.
• Explore conserved mechanisms in immunity-associated sirtuins.

Main Methods:

• Protein purification and in vitro enzymatic assays.
• Cellular localization and filament formation studies (in vitro and in vivo).
• Overexpression of wild-type and mutant FAM118B/FAM118A in human cells.

Main Results:

• FAM118B and FAM118A identified as vertebrate sirtuins with conserved filament formation.
• Individual NAD-processing activity is weak, but interaction significantly enhances it.
• Overexpression of wild-type FAM118B/FAM118A reduces cellular NAD levels, dependent on catalytic activity and filament formation.

Conclusions:

• Filament formation is a key feature of FAM118B and FAM118A, conserved across vertebrates.
• Enzyme interaction regulates NAD processing, suggesting a sophisticated control mechanism.
• These findings reveal conserved mechanisms of filament formation and NAD processing in immunity-associated sirtuins.