Ancestral immunity: the immune modules shared across domains of life.

Summary:

Various eukaryotic actors of immunity are thought to have evolved from prokaryotic antiphage proteins, with which they display sequence and/or structural similarity. The extent of defence mechanisms conservation between bacteria and eukaryotes, and how it could be harnessed to illuminate eukaryotic immunology, remains unknown. We use phylogeny-based bioinformatics to uncover novel eukaryotic immune proteins by searching for homologs of bacterial antiphage systems. We identify SIRal, a human protein with a SIRim domain (subtype of SIR2) and demonstrate that it plays a pivotal role in the animal TLR pathway of innate immunity, by mediating the transcriptional upregulation of proinflammatory genes downstream of TLR stimulation. By doing so, SIRal thwarts bacterial and viral infections. In addition to documenting the striking prokaryote/eukaryote immune conservation, our work illustrates how comparative genomics of defence mechanisms across different domains of life can be employed to uncover novel defence genes in humans.