AIM2-Like Receptors Positively and Negatively Regulate the Interferon Response Induced by Cytosolic DNA.

Yuki Nakaya,Spyridon Stavrou,Eileen A Moran,Susan R Ross,Jingtao Lilue,Christine A Biron

doi:10.1128/mbio.00944-17

Yuki Nakaya, Spyridon Stavrou + Show 4 more

Open Access

https://doi.org/10.1128/mbio.00944-17

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Abstract

ABSTRACTCytosolic DNAs derived from retrotransposons serve as pathogen-associated molecular patterns for pattern recognition receptors (PRRs) that stimulate the induction of interferons (IFNs) and other cytokines, leading to autoimmune disease. Cyclic GMP-AMP synthase is one PRR that senses retrotransposon DNA, activating type I IFN responses through the stimulator of IFN genes (STING). Absent in melanoma 2 (AIM2)-like receptors (ALRs) have also been implicated in these pathways. Here we show that the mouse ALR IFI205 senses cytosolic retrotransposon DNA independently of cyclic GMP-AMP production. AIM2 antagonizes IFI205-mediated IFN induction activity by sequestering it from STING. We also found that the complement of genes located in the ALR locus in C57BL/6 and AIM2 knockout mice are different and unique, which has implications for interpretation of the sensing of pathogens in different mouse strains. Our data suggest that members of the ALR family are critical to the host IFN response to endogenous DNA.

Highlights

Cytosolic DNAs derived from retrotransposons serve as pathogen-associated molecular patterns for pattern recognition receptors (PRRs) that stimulate the induction of interferons (IFNs) and other cytokines, leading to autoimmune disease
We showed that reverse-transcribed DNA generated during murine leukemia virus (MLV) infection of macrophages was sensed by cyclic GMP-AMP synthase (cGAS), DEAD box helicase 41 (DDX41), and the mouse ALR IFI203 [39, 40]
To determine which molecules are involved in the response to endogenous DNA in macrophages, we carried out a targeted small interfering RNA screening of a panel of genes implicated as cytosolic DNA sensors in the mouse macrophage cell line NR9456; cytosolic sensing in response to exogenous murine retrovirus infection and intact Toll-like receptor pathways in response to arenavirus infection are intact in this cell line [39,40,41]

Summary

Introduction

Cytosolic DNAs derived from retrotransposons serve as pathogen-associated molecular patterns for pattern recognition receptors (PRRs) that stimulate the induction of interferons (IFNs) and other cytokines, leading to autoimmune disease. AIM2 binding to dsDNA leads to induction of the inflammasome pathway [25, 31, 32] Another human ALR, the IFN-inducible 16 (IFI16) protein, functions as a dsDNA sensor for the induction of type I IFN and inflammasome activation against pathogens [33,34,35,36,37,38]. We show that the mouse ALR IFI205 senses self DNA derived from retrotransposons in the cytoplasm of macrophages and activates the type I IFN signaling pathway via STING. AIM2 dampened the self DNA-sensing pathway, likely by sequestering IFI205 from STING These studies are in contrast to a recent publication describing knockout mice lacking the entire Alr locus, including Aim, suggesting that ALRs play no role in the recognition of endogenous DNA [27]. We suggest instead that ALRs, including IFI205 and AIM2, function together with cGAS as positive and negative regulators of the innate immune response to cytosolic self DNAs

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