A widespread NADase domain links bacterial immunity with human TEP1

Abstract

Recent discoveries on bacterial immunity have revealed that several protein domains involved in anti-phage defense are conserved in eukaryotes, such as SIRim, TIR, PNP and gasdermin. Bacterial immune systems therefore have the potential to illuminate fundamental biological mechanisms throughout the tree of life. Here, we report that DUF4062 domains - which we rename NIR (NADase in bacterial immunity and vault ribonucleoproteins) - function in bacterial immunity against phages. We first identified NIR as an effector of Avs defense proteins, where it depletes cellular NAD+ to block viral infection. We then show that NIR domains are recurrently found as effectors in diverse defense systems. We use this association to uncover Vulcan and Vesta, two defense systems which trigger NAD+ depletion upon sensing distinct viral signals. Remarkably, NIR domains are widespread in eukaryotes where they are embedded in multiple NLR-like proteins. In particular, we identified a NIR domain with conserved NADase activity in the human TEP1 protein, a component of the telomerase complex and vault ribonucleoproteins. Together, these findings reveal an enzymatic activity shared between bacterial immunity and enigmatic eukaryotic machineries.