New progress in research on natural immune response mechanisms
September 06, 2015 Source: Bio Valley
Window._bd_share_config={ "common":{ "bdSnsKey":{ },"bdText":"","bdMini":"2","bdMiniList":false,"bdPic":"","bdStyle":" 0","bdSize":"16"},"share":{ }};with(document)0[(getElementsByTagName('head')[0]||body).appendChild(createElement('script')) .src='http://bdimg.share.baidu.com/static/api/js/share.js?v=89860593.js?cdnversion='+~(-new Date()/36e5)];Recently, the international academic journal Journal of Molecular Cell Biology published the latest research results from the Institute of Biophysics of the Chinese Academy of Sciences, the United States UCLA, Kunming Medical University and the Qingdao Bioenergy and Process Institute: "New insights into the structural basis of DNA recognition By HINa and HINb domains of IFI16", this study illustrates the structural basis of the downstream signaling pathway for DNA activation in the HI16 domain of the important immune signaling protein.
Innate immune (also known as "intrinsic immunity" or "non-specific immunity") systems are highly conserved among invasive microorganisms such as bacteria and viruses, and do not exist in health through pattern-recognition receptors (PRRs). The pathogen-associated molecular patterns (PAMPs) in the host cells are specifically recognized to perceive foreign microbial invasion and activate various intracellular signaling pathways and gene expression to initiate the body's immune response. Infection with DNA viruses or pathogenic bacteria, as well as impaired host cells or escaped apoptotic cells entering the cytoplasm and releasing double-stranded DNA can stimulate the innate immune response and promote the production of type I interferons to eliminate pathogens. Nucleic acids are the most important PAMPs in the process of viral infection.
In recent years, the identification of nucleic acid of genetic material of pathogenic microorganisms by PRRs has become a hot spot in natural immunology research. The recognition mechanism and signaling pathway of cytoplasmic DNA have been continuously improved, and DNA receptor factors such as DAI, AIM2, RNA polymerase III, LRRFIP1, IFI16, DDX41, DNA-PKC, and cGAS have been successively discovered. Among them, AIM2 (absent in melanoma 2) and IFI16 (interferon, gamma-inducible protein 16) are members of the PHYIN (also known as HIN-200, the interferon-inducible p200-protein) protein family. Based on the previous analysis of the AIM2 HIN domain and the double-stranded DNA complex, the researchers analyzed the IFI16 HIN domain complex. Although single-stranded DNA is used for screening of complex crystals, DNA appears to undergo self-annealing during crystallization, so that the single-stranded DNA complex structure of the IFI16 HINa domain shows that the protein binds to double-stranded DNA. By comparing with the structure of the HINb domain complex, we found that the overall structure of the two HIN domains of IFI16 is similar, but has different DNA binding surfaces. The HINb domain binds to the DNA backbone via the linker region and the amino acid of OB2 fold, and the HINa domain binds DNA via the amino acids on the two OB folds. The most striking difference between the two is that a HINb domain molecule interacts with both strands of DNA, while a HINa domain molecule specifically binds only one DNA strand. This finding confirms the unique function of HINa to bind to single-stranded DNA. Interestingly, the HINb domain deletion mutation of IFI16 attenuated the induction of IFN-β, while the HINa mutant with reduced DNA binding capacity increased IFN-β production. These results provide a basis for elucidating the function of the IFI16 HIN domain in DNA recognition and the activation of IFI16-mediated innate immune responses.
The researcher Liu Zhijie is the last correspondent author, Professor UCLA Cheng Genhong and Biophysical Institute Ouyang Song are co-communication authors. Researcher Feng Yingang of Qingdao Bioenergy and Process Institute of Chinese Academy of Sciences also made important contributions to this research. The research was funded by the Ministry of Science and Technology 973 project, major scientific and technological project on infectious disease prevention and control, the National Natural Science Foundation of China, the Chinese Academy of Sciences and the Beijing Municipal Science and Technology Commission.
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