Porcine NLRC3 specially binds short dsDNA to regulate cGAS activation
Minjie Li,
Cheng Zhu,
Ye Yuan,
Xiangyu Huang,
Lei Wu,
Jiayang Wu,
Hongyan Yin,
Lvye Chai,
Weiyu Qu,
Ya Yan,
Pingwei Li,
Xin Li
Affiliations
Minjie Li
National Key Laboratory of Veterinary Public Health and Safety, China Agricultural University, Beijing 100193, China; Key Laboratory of Animal Epidemiology of the Ministry of Agriculture and Rural Affairs, College of Veterinary Medicine, China Agricultural University, Beijing, China
Cheng Zhu
Tianjin Key Laboratory of Function and Application of Biological Macromolecular Structures, School of Life Sciences, Tianjin University, Tianjin 300072, China
Ye Yuan
National Key Laboratory of Veterinary Public Health and Safety, China Agricultural University, Beijing 100193, China; Key Laboratory of Animal Epidemiology of the Ministry of Agriculture and Rural Affairs, College of Veterinary Medicine, China Agricultural University, Beijing, China
Xiangyu Huang
National Key Laboratory of Veterinary Public Health and Safety, China Agricultural University, Beijing 100193, China; Key Laboratory of Animal Epidemiology of the Ministry of Agriculture and Rural Affairs, College of Veterinary Medicine, China Agricultural University, Beijing, China
Lei Wu
National Key Laboratory of Veterinary Public Health and Safety, China Agricultural University, Beijing 100193, China; Key Laboratory of Animal Epidemiology of the Ministry of Agriculture and Rural Affairs, College of Veterinary Medicine, China Agricultural University, Beijing, China
Jiayang Wu
Tianjin Key Laboratory of Function and Application of Biological Macromolecular Structures, School of Life Sciences, Tianjin University, Tianjin 300072, China
Hongyan Yin
National Key Laboratory of Veterinary Public Health and Safety, China Agricultural University, Beijing 100193, China; Key Laboratory of Animal Epidemiology of the Ministry of Agriculture and Rural Affairs, College of Veterinary Medicine, China Agricultural University, Beijing, China
Lvye Chai
National Key Laboratory of Veterinary Public Health and Safety, China Agricultural University, Beijing 100193, China; Key Laboratory of Animal Epidemiology of the Ministry of Agriculture and Rural Affairs, College of Veterinary Medicine, China Agricultural University, Beijing, China
Weiyu Qu
National Key Laboratory of Veterinary Public Health and Safety, China Agricultural University, Beijing 100193, China; Key Laboratory of Animal Epidemiology of the Ministry of Agriculture and Rural Affairs, College of Veterinary Medicine, China Agricultural University, Beijing, China
Ya Yan
National Key Laboratory of Veterinary Public Health and Safety, China Agricultural University, Beijing 100193, China; Key Laboratory of Animal Epidemiology of the Ministry of Agriculture and Rural Affairs, College of Veterinary Medicine, China Agricultural University, Beijing, China
Pingwei Li
Department of Biochemistry and Biophysics, Texas A&M University, College Station, TX, USA
Xin Li
National Key Laboratory of Veterinary Public Health and Safety, China Agricultural University, Beijing 100193, China; Key Laboratory of Animal Epidemiology of the Ministry of Agriculture and Rural Affairs, College of Veterinary Medicine, China Agricultural University, Beijing, China; Corresponding author
Summary: 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.
