The AIM2-like Receptors Are Dispensable for the Interferon Response to Intracellular DNA

Detection of intracellular DNA triggers activation of the STING-dependent interferon-stimulatory DNA (ISD) pathway, which is essential for antiviral responses. Multiple DNA sensors have been proposed to activate this pathway, including AIM2-like receptors (ALRs). Whether the ALRs are essential for activation of this pathway remains unknown. To rigorously explore the function of ALRs, we generated mice lacking all 13 ALR genes. We found that ALRs are dispensable for the type I interferon (IFN) response to transfected DNA ligands, DNA virus infection, and lentivirus infection. We also found that ALRs do not contribute to autoimmune disease in the Trex1−/− mouse model of Aicardi-Goutières Syndrome. Finally, CRISPR-mediated disruption of the human AIM2-like receptor IFI16 in primary fibroblasts revealed that IFI16 is not essential for the IFN response to human cytomegalovirus infection. Our findings indicate that ALRs are dispensable for the ISD response and suggest that alternative functions for these receptors should be explored. •Generated mice lacking all 13 mouse ALR genes to explore the function of ALRs•ALRs are not required for the ISD response or autoimmune disease in Trex1−/− mice•The human ALR IFI16 is not essential for the IFN response to HCMV infection.•ALR gene expression is altered in Aim2–/– (B6.129) cells due to 129-derived SNPs Detection of intracellular DNA triggers an antiviral type I interferon response. Multiple DNA sensors have been proposed to trigger this response, including AIM2-like receptors (ALRs). Gray and colleagues generated mice lacking all 13 mouse ALR genes and show that ALRs are dispensable for the interferon response to intracellular DNA.