Chen, F., Chen, Z., Tan, Y., Shen, X.Y., Leong, M., Yang, J.Y., Li, W.H., Hou, Y.N., Bao, G., Chen, Y.J., Ma, Y.R., Chan, T.F., Lee, H.C., Baeg, G.H., Zhang, D., Zhao, Y.J. (2026). Raw defines a TIR-fold cADPR hydrolase cooperating with dSarm in development and axon degeneration.  Cell Commun. Signal. 24(1): 437.

FBrf0266169

Research paper

Conserved TIR domain proteins play essential roles in immune signaling, development, and neurodegeneration. SARM1/dSarm, the only known enzymatically active TIR protein in animals, has been established as a key regulator of axon degeneration through its NAD-consuming activity. Here, we identify Raw as a member of a distinct TIR protein family that functions as a cADPR-specific hydrolase. Biochemical and structural analyses show that Raw does not hydrolyze NAD, but instead hydrolyzes cADPR with high efficiency and specificity. Its two TIR domains are both required for activity and together form a putative catalytic pocket containing essential glutamate residues, while AxD-slow Raw mutations markedly reduce enzymatic activity. In axon degeneration, dSarm converts NAD to cADPR and Raw subsequently hydrolyzes cADPR, together promoting NAD depletion. In developmental contexts, however, the two enzymes oppositely regulate cADPR levels. In Drosophila S2 cells, cADPR elevation induced by dSarm overexpression or Raw knockdown upregulates development-related genes, including the JNK target gene Mmp1, and similar effects are observed with 8-Br-cADPR, suggesting a probable alternate cADPR signaling mechanism independent of calcium mobilization. Consistently, Raw knockdown in fly wing discs elevates JNK phosphorylation, alters developmental gene expression, and causes wing defects, phenotypes that are substantially rescued by Ask1 knockdown. Similarly, dSarm overexpression induces pupal lethality, which is also reversed by Ask1 suppression. These genetic interactions support a model in which dSarm- and Raw-mediated cADPR metabolism modulates Ask1/JNK signaling during development. Phylogenetic analysis reveals the co-occurrence of dSarm and Raw across species, with conserved cADPR-hydrolysis activity observed in C. elegans Olrn-1. These findings establish distinct yet cooperative roles of dSarm and Raw in cADPR signaling-mediated development and NAD depletion-driven axon degeneration.

PMC13455253 (PMC) (EuropePMC)