SIR2-mediated filament assembly activates the NLR-like protein Avs5 for bacterial antiviral defense.

Abstract

Like mammalian nucleotide-binding and oligomerization domain receptors (NLRs), bacterial NLR-like proteins mediate antiviral defense. Avs5, a representative of a large family of short bacterial NLR-like proteins, contains an N-terminal SIR2 effector, a central nucleotide-binding domain (NBD), and a C-terminal sensor domain. Whereas canonical inflammasome NLRs use NBD oligomerization to nucleate effector-domain filaments, Avs5 forms SIR2-mediated filaments that couple receptor assembly to NADase activation. In the resting state, ATP-bound Avs5 is monomeric and subsequently forms a SIR2-mediated dimer that likely represents an intermediate in a stepwise activation pathway. Upon activation, ATP-dependent conformational remodeling of the NBD promotes conversion of these dimers into active filaments. Structure-guided mutagenesis, biochemical assays, and functional analyses show that filament assembly is required for efficient NAD+ hydrolysis and antiphage defense. These findings reveal an effector-driven activation mechanism and extend the principles by which NLR proteins couple higher-order assembly to immune defense across domains of life.