A Franco-British team of scientists has explored two human proteins recently identified as immune enzymes. Structural studies
in vitro show that, in a cell infected by a virus for example, these enzymes can assemble into filaments capable of degrading a central molecule in metabolism. Inherited from bacterial ancestors, this mechanism serves as an alarm signal in humans, allowing the cell to react to pathogens.
To fight viruses, bacteria have over billions of years developed sophisticated defense systems. Among these, certain proteins called sirtuins play a sentinel role by targeting a molecule absolutely central to cell function: nicotinamide adenine dinucleotide or NAD. This coenzyme is present in all living cells, from bacteria to humans. Its main function is to serve as an electron carrier in the redox reactions of cellular metabolism.
Illustration image Pixabay When a bacterium detects that it is infected by a virus, sirtuins trigger an altruistic sacrifice: they consume NAD and kill the condemned cell before the virus has had time to multiply. However, the same cell suicide mechanism does not work in humans.
Until now, the human sirtuin family consisted of 7 members, which differ significantly from bacterial sirtuins. Instead of degrading NAD by hydrolysis, they use it as a cofactor for epigenetic regulation. An international team led by scientists from CNRS, the Institut Pasteur, Oxford, and Croatia has now identified two little-studied human proteins, FAM118B and FAM118A, as additional sirtuins that have diverged little from their bacterial ancestor.
Studying their structure at the atomic scale using cryo-electron microscopy shows that these two sirtuins are indeed close to bacterial sirtuins and have preserved NAD hydrolytic activity, making these proteins true "molecular fossils." Both
in vitro and in cells, FAM118B and FAM118A individually form homogeneous filaments, a characteristic shared with bacterial sirtuins involved in defense against phages.
Although FAM118B and FAM118A exhibit low enzymatic activity when isolated, their synergistic association triggers a strong consumption of NAD, revealing a cooperative mechanism apparently based on the formation of heterogeneous filaments in cells. Simultaneous overexpression of both proteins in human cells reduces NAD levels to about 15% of normal. Complementary experiments have shown that this effect disappears as soon as the catalytic sites of the enzymes are deactivated or their filament formation is prevented, suggesting that these two properties are inseparable from the immune function.
FAM118B being involved in certain chromosomal fusions observed in rare brain tumors, better understanding its ability to form filaments could shed light on still obscure oncogenic mechanisms. More broadly, this study, published in the journal
Nature Structural & Molecular Biology, shows how deeply human innate immunity is rooted in billion-year-old bacterial defenses, an evolutionary continuity that science is only beginning to decipher.
Editor: AVR