<p>Toll/interleukin-1 receptor (TIR) domain proteins are immune signalling components and function as NAD⁺-cleaving enzymes to activate defence responses. In plants, TIR activation triggers cell death and severely represses growth, especially under osmotic stress, while in animals, it promotes axon degeneration. However, the mechanisms regulating TIR suppression remain unclear. Here we show that TIR NADase activity requires a conserved serine residue spatially close to the catalytic glutamate. The osmotic-stress-activated plant Ca²⁺-dependent protein kinases (CPKs), the mammalian Ca²⁺/calmodulin-dependent protein kinase II delta (CAMK2D) and TANK-binding kinase 1 (TBK1) phosphorylate TIR domains at this conserved serine, which blocks TIR NADase activities and functions, thereby maintaining growth in plants and suppressing SARM1 TIR signalling in animals. Our findings define a fundamental molecular mechanism by which phosphorylation at a conserved serine residue inhibits TIR signalling in plants and animals and sustains plant growth.</p>