TeTIR domains define a new class of animal TIR-like NADase effectors in STAND proteins

TIR domains are found in diverse immune signaling proteins and, in several systems, function as NAD+-cleaving enzymes causing or signaling cell death. In plants, TIR domains occur as effector domains in TNL immune receptors, where they are coupled to a central STAND ATPase and a C-terminal repeat domain. Here, we identify TeTIR (TEP1 extended TIR), a previously unrecognized family of TIR-like domains associated with NACHT-type ATPases and C-terminal WD40 or TPR repeat domains. The TeTIR domain of human TEP1 exhibits robust NADase activity comparable to SARM1-TIR, making TEP1 the only other NADase-active TIR-like protein identified in mammals. NADase activity is conserved in TEP1 homologs from diverse eukaryotes. The crystal structure of TEP1 TeTIR reveals an extended TIR-like fold with additional secondary-structure elements and a distinctive RWG-containing loop. Molecular dynamics simulations indicate that the catalytic glutamate contributes to catalysis and the conformational equilibrium of the active-site region, promoting formation of a substrate-accessible state. Structure-guided mutagenesis identifies conserved residues contributing to NAD+ recognition and catalysis, including features distinct from canonical TIR NADases. Expression of isolated TEP1 TeTIR causes NAD+ depletion and cell death in a catalytic-glutamate-dependent manner. TeTIRs thus define a distinct family of animal TIR-like NADases embedded in NACHT-type STAND architectures.