Abstract
Many human cells can sense the presence of exogenous DNA during infection though the cytosolic DNA receptor cyclic GMP-AMP synthase (cGAS), which produces the second messenger cyclic GMP-AMP (cGAMP). Other putative DNA receptors have been described, but whether their functions are redundant, tissue-specific or integrated in the cGAS-cGAMP pathway is unclear. Here we show that interferon-γ inducible protein 16 (IFI16) cooperates with cGAS during DNA sensing in human keratinocytes, as both cGAS and IFI16 are required for the full activation of an innate immune response to exogenous DNA and DNA viruses. IFI16 is also required for the cGAMP-induced activation of STING, and interacts with STING to promote STING phosphorylation and translocation. We propose that the two DNA sensors IFI16 and cGAS cooperate to prevent the spurious activation of the type I interferon response.
Highlights
Many human cells can sense the presence of exogenous DNA during infection though the cytosolic DNA receptor cyclic GMP-AMP synthase, which produces the second messenger cyclic GMP-AMP
The presence of cyclic GMP-AMP synthase (cGAS) is central for DNA sensing in keratinocytes, as it is in other cell types, interferon-g inducible protein 16 (IFI16) is closely integrated into the cGAS-cyclic GMP-AMP (cGAMP)-STING signalling pathway by promoting the activation of STING in synergy with cGAMP
The function of IFI16 as a receptor for foreign DNA during infection with DNA viruses and intracellular bacteria is supported by a large body of evidence, mostly relying on the use of RNA interference (RNAi) approaches[42]
Summary
Many human cells can sense the presence of exogenous DNA during infection though the cytosolic DNA receptor cyclic GMP-AMP synthase (cGAS), which produces the second messenger cyclic GMP-AMP (cGAMP). We show that interferon-g inducible protein 16 (IFI16) cooperates with cGAS during DNA sensing in human keratinocytes, as both cGAS and IFI16 are required for the full activation of an innate immune response to exogenous DNA and DNA viruses. IFI16 is required for the response to infection with retroviruses such as HIV-1 in macrophages[18] as well as to infection with intracellular bacteria such as Listeria monocytogenes in human myeloid cells[19], and Francisella novicida in mouse macrophages[20] In many of these cases, an essential role for cGAS has been observed in the same cell type, during infection with the same pathogen or following stimulation with identical DNA ligands[15,18,19,20,21]. We propose that cGAS does not act in isolation, but rather cooperates with other factors such as IFI16 to activate STING in human cells
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