Abstract
The innate immunity DNA sensors have drawn much attention due to their significant importance against the infections with DNA viruses and intracellular bacteria. Among the multiple DNA sensors, IFI16, and cGAS are the two major ones, subjected to extensive studies. However, these two DNA sensors in livestock animals have not been well defined. Here, we studied the porcine IFI16 and cGAS, and their mutual relationship. We found that both enable STING-dependent signaling to downstream IFN upon DNA transfection and HSV-1 infection, and cGAS plays a major role in DNA signaling. In terms of their relationship, IFI16 appeared to interfere with cGAS signaling as deduced from both transfected and knockout cells. Mechanistically, IFI16 competitively binds with agonist DNA and signaling adaptor STING and thereby influences second messenger cGAMP production and downstream gene transcription. Furthermore, the HIN2 domain of porcine IFI16 harbored most of its activity and mediated cGAS inhibition. Thus, this study provides a unique insight into the porcine DNA sensing system.
Highlights
The innate immune system acts as the first line of host defense and senses multiple danger signals from pathogens by recognizing the pathogen-associated molecular patterns (PAMPs) [1]
The PAMPs and damage-associated molecular patterns (DAMPs) are both recognized by innate immune pattern recognition receptors (PRRs), which include Toll-like receptors (TLRs), RIG-I-like receptors (RLRs), NOD-like receptors (NLRs), C-type lectin like receptors (CLRs), and cytosolic DNA receptors (CDRs)
The pcDNA expression constructs of porcine cGAS and IFI16 were transfected into 293T cells and Porcine alveolar macrophages (PAMs), and their expressions were examined by Western blotting and IFA using the anti-HA antibody
Summary
The innate immune system acts as the first line of host defense and senses multiple danger signals from pathogens by recognizing the pathogen-associated molecular patterns (PAMPs) [1]. It detects damage-associated molecular patterns (DAMPs) to maintain homeostasis [1, 2]. The PAMPs and DAMPs are both recognized by innate immune pattern recognition receptors (PRRs), which include Toll-like receptors (TLRs), RIG-I-like receptors (RLRs), NOD-like receptors (NLRs), C-type lectin like receptors (CLRs), and cytosolic DNA receptors (CDRs). The PRRs trigger intracellular signaling to initiate either gene transcription or protease-dependent cytokine secretion, resulting in the production of anti-viral interferons (IFNs), proinflammatory cytokines, and chemokines to directly combat pathogens and shape subsequent adaptive immunity.
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