Editors' ChoiceImmunology

Taking the STING out of infection

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Science Signaling  18 Aug 2015:
Vol. 8, Issue 390, pp. ec229
DOI: 10.1126/scisignal.aad2482

In response to infection, cells activate an innate immune response that involves proteins that sense pathogen-associated molecular patterns (PAMPs) or molecules, such as the cyclic dinucleotide cGAMP, produced by the host in response to detection of such PAMPs. STING is a PAMP sensor that is associated with the surface of the endoplasmic reticulum (ER) in uninfected cells and traffics through the Golgi to autophagosomes, where it is ultimately degraded, in cells infected with viruses or bacteria, such as Shigella. Shigella injects IpaJ, which inhibits ER to Golgi transport, and VirA, which inhibits transport through the Golgi. Dobbs et al. engineered strains of Shigella that lacked either of these two proteins or engineered strains of Listeria to produce either of these proteins and examined the trafficking of STING and downstream signaling events associated with STING activation when these bacteria infected mouse embryonic fibroblasts (MEFs). Compared with cells infected with wild-type Shigella or Shigella ΔvirA, infection with Shigella ΔipaJ increased STING-dependent interferon b (Infb) expression; infection with Listeria expressing IpaJ disrupted the structure of the Golgi and reduced Infb expression. Analysis of the trafficking of a fusion protein of STING and green fluorescent protein (GFP) engineered in Sting –/– MEFs that were injected with recombinant IpaJ, a catalytically inactive mutant of IpaJ that does not disrupt ER trafficking, or VirA revealed that IpaJ trapped STING-GFP in the ER in a manner dependent on IpaJ catalytic activity and that VirA trapped STING-GFP in ERGIC, a compartment between the ER and Golgi. STING recruits and activates the downstream kinase TBK1. Compared with MEFs infected with wild-type Shigella, the colocalization of STING-GFP and TBK1, as well as TBK1 phosphorylation and activity, was increased in MEFs infected with Shigella ΔipaJ; infection with Listeria expressing IpaJ resulted in reduced TBK1 activity compared with infection with wild-type Listeria. Reconstitution of Sting –/– MEFs with versions of mouse STING-GFP with mutations homologous to those found in patients with autoimmune disease revealed that these mutants localized to the ERGIC and Golgi in the absence of infection and that transfection with double-stranded DNA (to stimulate the STING-mediated immune response) failed to promote the trafficking of the mutant versions out of the Golgi, resulting in enhanced stability of the mutant STING proteins. These results not only shed light on the mechanisms regulating STING activity, but also provide a molecular basis for autoimmune disease in patients with specific STING mutations (see Hiller and Hornung).

N. Dobbs, N. Burnaevskiy, D. Chen, V. K. Gonugunta, N. M. Alto, N. Yan, STING activation by translocation from the ER is associated with infection and autoinflammatory disease. Cell Host Microbe 18, 157–168 (2015). [PubMed]

B. Hiller, V. Hornung, STING signaling the enERGIC way. Cell Host Microbe 18, 137–139 (2015). [PubMed]