The ER membrane adaptor ERAdP senses the bacterial second messenger c-di-AMP and initiates anti-bacterial immunity.

Cyclic diadenylate monophosphate (c-di-AMP) is secreted by bacteria as a secondary messenger. How immune cells detect c-di-AMP and initiate anti-bacterial immunity remains unknown. We found that the endoplasmic reticulum (ER) membrane adaptor ERAdP acts as a direct sensor for c-di-AMP. ERAdP-deficient mice were highly susceptible to Listeria monocytogenes infection and exhibited reduced pro-inflammatory cytokines. Mechanistically, c-di-AMP bound to the C-terminal domain of ERAdP, which in turn led to dimerization of ERAdP, resulting in association with and activation of the kinase TAK1. TAK1 activation consequently initiated activation of the transcription factor NF-κB to induce the production of pro-inflammatory cytokines in innate immune cells. Moreover, double-knockout of ERAdP and TAK1 resulted in heightened susceptibility to L. monocytogenes infection. Thus, ERAdP-mediated production of pro-inflammatory cytokines is critical for controlling bacterial infection.