NAD+ depletion by catalytic TIR domains triggers a distinct form of regulated necrosis in mammalian cells.

Proteins containing Toll/interleukin-1 receptor (TIR) domains with catalytic NADase activity have recently emerged as major regulators of innate immunity in both bacteria and plants. In humans, however, only a single protein-SARM1-exhibits TIR-dependent NADase activity. Initially reported to act as a negative regulator of Toll-like receptor (TLR) signaling, SARM1-mediated NAD+ hydrolysis is now recognized as the central driver of Wallerian degeneration, a regulated form of axonal cell death that occurs following injury. Here, we demonstrate that suppression of TLR signaling by SARM1 requires its NADase activity and correlates with the induction of host cell death. Furthermore, we show that immune suppression by the Staphylococcus aureus effector TirS similarly relies on its ability to hydrolyze NAD+ and induce host cell death. Further analysis of TIR-induced cell death shows that it constitutes a form of regulated necrosis that is independent of known programmed cell death pathways. Comparative analysis of a panel of animal, bacterial, and plant TIR domains reveals that, in mammalian cells, TIR-induced cell death primarily results from the depletion of cellular NAD+ levels, and not from the accumulation of specific NAD+ hydrolysis products. Together, these findings implicate NAD+ depletion and the induction of host cell death as the main mechanism by which catalytic TIR domains suppress innate immunity.