Conserved catalytic activity of animal TIR domains functions in TLR4 signaling

The TIR domain of human TLR4 is an enzyme that produces cyclic ADP-ribose, and its catalytic glutamate is required for LPS-driven TLR4 signaling in human macrophages.

• Why it matters: Animal TIR domains were mainly viewed as protein-interaction adaptors, but bacterial and plant work suggested enzymatic roles; this study tests whether catalytic activity is conserved in animals.
• What they did: They assayed TIR domains from evolutionarily diverse animals for cyclic ADP-ribose production and used glutamate substitution in the human TLR4 TIR domain, then measured LPS-induced inflammatory responses and Myddosome assembly in human macrophages.
• The result: Catalytic activity is conserved across animals, and abolishing the TLR4 TIR catalytic residue eliminates LPS-induced inflammatory responses and disrupts Myddosome assembly, supporting a functional requirement for the conserved catalytic site.

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