A human homolog of SIR2 antiphage proteins mediates immunity via the TLR pathway

The full extent of immune system conservation between prokaryotes and eukaryotes is unknown. However, recent research supports that a subset of bacterial antiphage proteins is conserved in eukaryotes and likely gave rise to key actors of mammalian immunity. Here, we show that the SIR2 protein domain, present in bacterial antiphage systems, plays a role in eukaryotic innate immunity. Through phylogenetic analysis, we identify SIRanc, a human protein with a SIRim domain (subtype of SIR2). We demonstrate that SIRanc plays a pivotal role in the animal toll-like receptor (TLR) pathway of innate immunity by mediating the transcriptional upregulation of proinflammatory genes downstream of TLR stimulation. This depends on the enzymatic activity of SIRanc, which degrades NAD ⁺ , a central cellular metabolite. Finally, we show that proteins with a SIRim domain are diverse and widespread, detected in 19% of eukaryotic genomes, with SIRanc representing one of the five sirim lineages. This work opens avenues of research on the potential role of eukaryotic SIRim proteins in immunity, as well as on the involvement of SIRanc in human pathology.