The SARM1 TIR NADase: Mechanistic Similarities to Bacterial Phage Defense and Toxin-Antitoxin Systems

Abstract

The Toll/interleukin-1 receptor (TIR) domain is the signature signalling motif of innate immunity, with essential roles in innate immune signalling in bacteria, plants, and animals. TIR domains canonically function as scaffolds, with stimulus-dependent multimerization generating binding sites for signalling molecules such as kinases and ligases that activate downstream immune mechanisms. Recent studies have dramatically expanded our understanding of the TIR domain, demonstrating that the primordial function of the TIR domain is to metabolize NAD+. Mammalian SARM1, the central executioner of pathological axon degeneration, is the founding member of the TIR-domain class of NAD+ hydrolases. This unexpected NADase activity of TIR domains is evolutionarily conserved, with archaeal, bacterial, and plant TIR domains all sharing this catalytic function. Moreover, this enzymatic activity is essential for the innate immune function of these proteins. These evolutionary relationships suggest a link between SARM1 and ancient self-defense mechanisms that has only been strengthened by the recent discovery of the SARM1 activation mechanism which, we will argue, is strikingly similar to bacterial toxin-antitoxin systems. In this brief review we will describe the regulation and function of SARM1 in programmed axon self-destruction, and highlight the parallels between the SARM1 axon degeneration pathway and bacterial innate immune mechanisms.

The injured sciatic nerve atlas (iSNAT), insights into the cellular and molecular basis of neural tissue degeneration and regeneration

“…Because WD results in axon disintegration and simultaneous breakdown of myelin sheaths into ovoids, it is not clear whether myelin debris, SC activation, or axon fragmentation is the main trigger for WD-associated nerve inflammation. While Sarm1 is best known for its vital role in axon degeneration, evidence suggests that Sarm1 functions in myeloid cells to regulate innate immunity ( DiAntonio et al, 2021 ; Waller and Collins, 2022 ). We used parabiosis to show that similar to Sarm1-/- Mac, wildtype Mac fail to accumulate in the distal nerve of injured Sarm1-/- mice, indicating that reduced inflammation is not due to loss of Sarm1 in Mac.…”

NAD+, Axonal Maintenance, and Neurological Disease

“…SARM1 was originally annotated as the fifth member of the myeloid differentiation primary response gene 88 (MyD88) family of mammalian proteins that are distinguished by their C-terminal TIR domain and are thought to act as immune adaptor proteins for Toll-like receptor signaling (Carty et al, 2006 ; Kim et al, 2007 ). However, the unexpected discovery of its NADase activity (Essuman et al, 2017 ) that is unique among MyD88 proteins places SARM1 within a larger, diverse family of TIR-domain proteins with important roles in innate immunity, from bacteria and plants to humans (DiAntonio et al, 2021 ). The intrinsic NADase activity of these proteins serves as a defense mechanism against pathogens by depleting intracellular NAD + levels and causing cell death (DiAntonio et al, 2021 ; Wan et al, 2019 ).…”

“…However, the unexpected discovery of its NADase activity (Essuman et al, 2017 ) that is unique among MyD88 proteins places SARM1 within a larger, diverse family of TIR-domain proteins with important roles in innate immunity, from bacteria and plants to humans (DiAntonio et al, 2021 ). The intrinsic NADase activity of these proteins serves as a defense mechanism against pathogens by depleting intracellular NAD + levels and causing cell death (DiAntonio et al, 2021 ; Wan et al, 2019 ).…”

Targeting NAD+ metabolism: dual roles in cancer treatment

“…Notably, NAM also suppresses other NAD + -consuming enzymes ( 121 , 122 ). Furthermore, its enzymatic activity is essential for bacterial innate immunity ( 123 ). However, in contrast to its undisputed pivotal role in axonal degeneration, the immunoregulatory role of NAM remains unclear.…”