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Published on: December 26, 2020
Porcine NLRC3 specially binds short dsDNA to regulate cGAS activation
Minjie Li1,2, Cheng Zhu3, Ye Yuan1,2
1National Key Laboratory of Veterinary Public Health and Safety, China Agricultural University, Beijing 100193, China.
Abstract:
Host immune system has evolved multiple sensors to detect pathogenic and damaged DNA, where precise regulation is critical for distinguishing self from non-self. Our previous studies showed that NLRC3 is an inhibitory nucleic acid sensor that binds to viral DNA and thereby unleashing STING activation. In this study, we demonstrate that human NLRC3 favors long dsDNA, while porcine NLRC3 shows an affinity for shorter dsDNA. Mechanistically, a conserved arginine residue within the leucine-rich repeats of primates NLRC3 forms a structural bridge facilitating the binding of long dsDNA. Conversely, a glycine residue that replaces the arginine in non-primates disrupts this bridge. Furthermore, porcine NLRC3 negatively regulates type I interferon by interacting with cyclic GMP-AMP synthase (cGAS) to inhibit its DNA binding, thereby preventing cGAS activation. These results reveal an unrecognized mechanism by which a species-specific amino acid variation of NLRC3 influences nucleic acid recognition, providing insights into the evolution of innate immunity to pathogens.
Insights
Host immune systems use NLRC3 sensors to detect DNA. Species-specific variations in NLRC3 affect DNA binding, influencing innate immunity and the evolution of pathogen defense.
Area of Science:
- Immunology
- Molecular Biology
- Genetics
Background:
- The host immune system relies on nucleic acid sensors to detect foreign DNA, with precise regulation crucial for self/non-self discrimination.
- NLRC3 acts as an inhibitory nucleic acid sensor, previously shown to bind viral DNA and trigger STING activation.
Purpose of the Study:
- To investigate the species-specific differences in NLRC3's DNA binding preferences.
- To elucidate the molecular mechanisms underlying these variations and their impact on innate immune responses.
Main Methods:
- Comparative analysis of human and porcine NLRC3 binding affinities for different lengths of double-stranded DNA (dsDNA).
- Structural analysis to identify key amino acid residues responsible for dsDNA recognition.
- Investigation of NLRC3's interaction with cyclic GMP-AMP synthase (cGAS) and its effect on cGAS activation and type I interferon production.
Main Results:
- Human NLRC3 preferentially binds long dsDNA, while porcine NLRC3 binds shorter dsDNA.
- A conserved arginine residue in primate NLRC3 facilitates long dsDNA binding, whereas a glycine residue in non-primates disrupts this interaction.
- Porcine NLRC3 inhibits type I interferon production by preventing cGAS from binding to DNA, thus suppressing cGAS activation.
Conclusions:
- Species-specific amino acid variations in NLRC3 significantly alter its nucleic acid recognition capabilities.
- These variations represent an unrecognized mechanism influencing innate immunity evolution against pathogens.
- Understanding these differences provides insights into host-pathogen interactions and immune system adaptation.
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