Raw defines a TIR-fold cADPR hydrolase cooperating with dSarm in development and axon degeneration - PubMed
3 hours ago
- #cADPR signaling
- #TIR domain enzymes
- #axon degeneration
- Raw is identified as a TIR-fold cADPR hydrolase distinct from SARM1/dSarm, which hydrolyzes NAD.
- Raw specifically hydrolyzes cADPR with high efficiency, requiring both TIR domains and glutamate residues for activity; mutations reduce its function.
- In axon degeneration, dSarm converts NAD to cADPR, and Raw then hydrolyzes cADPR, together driving NAD depletion.
- In development, Raw and dSarm oppositely regulate cADPR levels, influencing JNK signaling via Ask1 and affecting gene expression and wing formation in Drosophila.
- Genetic interactions show that Raw knockdown or dSarm overexpression leads to developmental defects, rescued by Ask1 suppression, linking cADPR metabolism to Ask1/JNK signaling.
- Phylogenetic analysis indicates co-occurrence of dSarm and Raw across species, with conserved cADPR hydrolysis in C. elegans Olrn-1, highlighting evolutionary conservation.