Toll/interleukin-1 receptor (TIR) domain-containing proteins have a crucial role in mammalian and plant innate immunity. TIR domain-containing proteins have also been reported in bacteria — for example, the Thoeris defence system. In a recent study, Sorek and colleagues describe the bacterial type IV Thoeris defence system, which contains both a TIR domain protein and a caspase-like protease. They showed that following phage infection, the TIR domain-containing protein produces a previously unknown signalling molecule that binds to the caspase-like protease, which leads to mass protein degradation and the inhibition of phage infection.

In human immunity, caspase proteins have important roles in mediating regulated cell death by cleaving cellular proteins in response to infection. Indeed, mass spectrometry of labelled proteins in cell lysates identified the essential translation elongation factor Tu (EF-Tu) as a newly cleaved protein in cells infected by phages. Western blot analysis confirmed cleavage of EF-Tu in cells expressing the TIR domain-containing protein and caspase-like protein, whereas the cleavage products were absent in cells expressing catalytically inactive mutant proteins. This suggested that the TIR domain-containing protein might activate the caspase-like protein, which results in the proteolytic cleavage of EF-Tu. However, further experiments revealed that the caspase-like protein does not specifically target EF-Tu, but rather acts as an arginine-specific protease that induces mass protein degradation.