Editors' ChoiceImmunology

Sensing bacterial infection

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Sci. Signal.  30 Jan 2018:
Vol. 11, Issue 515, eaat1224
DOI: 10.1126/scisignal.aat1224

The endoplasmic reticulum–resident adaptor protein ERAdP senses bacterial c-di-AMP to stimulate an immune response.

Cells detect invading viruses and bacteria through the sensing of pathogen-associated molecular patterns by pathogen-recognition receptors. The enzyme cGAS senses cytosolic DNA and generates the cyclic dinucleotide cGAMP, which binds to the endoplasmic reticulum (ER)–resident adaptor protein STING. This in turn leads to the production of type I interferons (IFNs), as well as proinflammatory cytokines. The cyclic dinucleotide c-di-AMP is a second messenger secreted by Gram-positive bacteria, such as Listeria monocytogenes, and it binds with less affinity to STING than does cGAMP, eliciting a weaker IFN response (see commentary by Jakobsen). Xia et al. found that mice deficient in another ER adaptor protein, ERAdP, and infected with L. monocytogenes died rapidly, whereas their wild-type counterparts produced more proinflammatory cytokines and cleared the pathogen. However, mice deficient in STING had normal cytokine production and were not susceptible to L. monocytogenes infection. ERAdP-deficient mouse macrophages showed defective proinflammatory cytokine production in response to L. monocytogenes infection or treatment with c-di-AMP. Precipitation studies showed that c-di-AMP bound to the C-terminal region of ERAdP, and c-di-AMP had a greater affinity for ERAdP than it had for STING. Binding of c-di-AMP stimulated ERAdP dimerization and recruitment of the kinase TAK1, which resulted in the activation of NF-κB and its translocation to the nucleus to drive the expression of genes encoding proinflammatory cytokines. Mice deficient in both ERAdP and TAK1 in myeloid cells failed to demonstrate NF-κB activation or cytokine production in response to L. monocytogenes infection and died more quickly than did their single knockout counterparts. Together, these data suggest that the detection of c-di-AMP by ERAdP is a critical mechanism by which to control bacterial infection.

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