9uga | pdb_00009uga
SARM1 senses DNA to promote NAD degradation
Structural highlights
FunctionSARM1_HUMAN Negative regulator of MYD88- and TRIF-dependent toll-like receptor signaling pathway which plays a pivotal role in activating axonal degeneration following injury. Promotes Wallerian degeneration an injury-induced axonal death pathway which involves degeneration of an axon distal to the injury site. Can activate neuronal death in response to stress. Regulates dendritic arborization through the MAPK4-JNK pathway. Involved in innate immune response. Inhibits both TICAM1/TRIF- and MYD88-dependent activation of JUN/AP-1, TRIF-dependent activation of NF-kappa-B and IRF3, and the phosphorylation of MAPK14/p38.[1] [2] [3] [4] Publication Abstract from PubMedDetection of DNA is a fundamental strategy for life to recognize non-self or abnormal-self to subsequently trigger the downstream responses. However, the mechanism underlying DNA sensing is incompletely understood. Here, we show that a key neural executioner, sterile alpha and Toll/interleukin-1 receptor (TIR) motif containing 1 (SARM1), senses double-stranded DNA (dsDNA) to promote cell death. dsDNA-bound and -activated SARM1 to degrade nicotinamide adenine dinucleotide (NAD(+)) in a sequence-independent manner. SARM1 bound dsDNA via the TIR domain, and lysine residues in the TIR domain contributed to dsDNA binding. In the cellular context, cytosolic dsDNA from dsDNA transfection or chemotherapy treatment was colocalized with SARM1 and activated SARM1 to elicit NAD(+) degradation and cell death, which was abrogated by SARM1 knockout or DNA-binding residue mutation. Consistently, SARM1 knockout blocked chemotherapy-induced neuropathy (CIN) in mice. Our results reveal SARM1 as a DNA sensor, which might be targetable for therapeutic interventions. SARM1 senses dsDNA to promote NAD(+) degradation and cell death.,Wang L, Liu Q, Li S, Wang N, Chen Y, Chen J, Wang L, Huang Y, Sun Z, Dong L, Li S, Liu Q, Gao S, Ma X, Song C, Yang Q Cell. 2025 Oct 24:S0092-8674(25)01126-2. doi: 10.1016/j.cell.2025.09.026. PMID:41138726[5] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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