Abstract
Antiviral defence systems frequently utilise cyclic nucleotide second messengers. A prominent example is the type III CRISPR-Cas system, which generates cyclic oligoadenylates (cOA) on detecting viral RNA. cOA molecules can bind and activate a wide range of effectors to provide antiviral defence. In both prokaryotes and higher plants, activation of a catalytic Toll/Interleukin Receptor (TIR) domain by multimerization results in degradation of NAD+, limiting cell metabolism and thus viral replication. Here, we describe a CRISPR-associated TIR-containing effector that includes a SAVED (SMODS-associated and fused to various effector domains) domain for nucleotide sensing and a cOA-degrading ring nuclease Crn4 domain. We demonstrate that the TIR-SAVED-Ring nuclease (TSR1) effector binds cA3, resulting in activation of the TIR NADase activity. The Crn4 domain, which imposes an unusual dimeric quaternary structure on the effector, degrades cA3, providing a mechanism to auto-deactivate the effector. TSR1 is thus a highly unusual example of a dimeric and self-limiting TIR effector in antiviral immunity.