SARM1-specific motifs in the TIR domain enable NAD⁺ loss and regulate injury-induced SARM1 activation

• Published in: Proceedings of the National Academy of Sciences - PNAS 2016-10, Vol.113 (41), p.E6271-E6280
• Main Authors: Summers, Daniel W., Gibson, Daniel A., DiAntonio, Aaron, Milbrandt, Jeffrey
• Format: Article
• Language: English
• Subjects: Adenosine Triphosphate - metabolism; Amino Acid Motifs; Amino Acid Sequence; Animals; Armadillo Domain Proteins - chemistry; Armadillo Domain Proteins - genetics; Armadillo Domain Proteins - metabolism; Axons - physiology; Biological Sciences; Cell Death; Cell Line; Cytokines; Cytoskeletal Proteins - chemistry; Cytoskeletal Proteins - genetics; Cytoskeletal Proteins - metabolism; Ganglia, Spinal - cytology; Gene Expression; Humans; Mice; Mice, Knockout; Models, Biological; Models, Molecular; Mutation; NAD - metabolism; Nematodes; Nerve Regeneration; Neurons; Neurons - physiology; PNAS Plus; Primary Cell Culture; Protein Interaction Domains and Motifs; Protein Multimerization; Protein Structure, Secondary; Proteins; Trauma
• ISSN: 0027-8424; 1091-6490
• DOI: 10.1073/pnas.1601506113

Axon injury in response to trauma or disease stimulates a self-destruction program that promotes the localized clearance of damaged axon segments. Sterile alpha and Toll/interleukin receptor (TIR) motif-containing protein 1 (SARM1) is an evolutionarily conserved executioner of this degeneration cascade, also known as Wallerian degeneration; however, the mechanism of SARM1-dependent neuronal destruction is still obscure. SARM1 possesses a TIR domain that is necessary for SARM1 activity. In other proteins, dimerized TIR domains serve as scaffolds for innate immune signaling. In contrast, dimerization of the SARM1 TIR domain promotes consumption of the essential metabolite NAD⁺ and induces neuronal destruction. This activity is unique to the SARM1 TIR domain, yet the structural elements that enable this activity are unknown. In this study, we identify fundamental properties of the SARM1 TIR domain that promote NAD⁺ loss and axon degeneration. Dimerization of the TIR domain from the Caenorhabditis elegans SARM1 ortholog TIR-1 leads to NAD⁺ loss and neuronal death, indicating these activities are an evolutionarily conserved feature of SARM1 function. Detailed analysis of sequence homology identifies canonical TIR motifs as well as a SARM1-specific (SS) loop that are required for NAD⁺ loss and axon degeneration. Furthermore, we identify a residue in the SARM1 BB loop that is dispensable for TIR activity yet required for injury-induced activation of full-length SARM1, suggesting that SARM1 function requires multidomain interactions. Indeed, we identify a physical interaction between the autoinhibitory N terminus and the TIR domain of SARM1, revealing a previously unrecognized direct connection between these domains that we propose mediates autoinhibition and activation upon injury.