The molecular mechanism of herpes virus immune escape and host natural immune regulation

immune response mediated by cytoplic nucleic acids play an important role in the process of resisting pathogen invasion, in which the phosphorylation modification of the joint protein STING and MAVS is necessary to activate the type I interferon reaction. If the natural immune response is too weak, the host is not able to effectively resist the invasion of pathogens; How are STING and MAVS-mediated signal paths precisely regulated? Do pathogens, especially viruses, manipulate this regulatory process? Is escape or antagonized host natural immunity conducive to the replication of the virus itself? What are the molecular mechanisms?
Recently, Deng Hongyu, a researcher at the
Institute of Biophysics in China, identified pPM1G, a host protein phosphatase PPM1G that negatively regulates the natural immune response mediated by STING and MAVS, and analyzed the molecular mechanism of the kaposi sarcoma-related herpes virus (KSHV) using the mesoglobin ORF33 to hold PPM1G for immune escape.
herpes virus is an ancient family of viruses that evolved a variety of strategies to suppress the host's natural immune response to infect cells and establish persistent latent infections. Interstellar protein is a class of structural proteins unique to herpes viruses, which, in addition to functioning during the assembly release phase in the late stages of virus replication, is also involved in regulating cell signaling path paths, especially the immune escape process, in the early stages of viral infection from the beginning. ORF33 is an interstational protein that is conservative in all herpes viruses, and studies by the team have shown that ORF33 plays a key role in the assembly of herpes virus particles, but it is not clear whether it has an immune escape function. The study found that the missing KSHV virus induced cells from ORF33 produced more IFN beta than wild viruses, and that ORF33 could be combined with STING and MAVS to inhibit STING and MAVS recruitment of IRF3 molecules. The results show that ORF33 inhibits the host's natural immune response by affecting the function of the joint proteins STING and MAVS.
, the study also found that in-cell expression orF33 significantly reduced phosphate levels in STING and MAVS. In in-body phosphatase experiments, only purified ORF33 proteins from lactating cells can reduce the phosphate levels of STING and MAVS, while primary nucleocytes can't express purified ORF33. This suggests that ORF33 may recruit and dephosphate STING and MAVS using the host protein phosphatase. Using immunopopulation-mass spectrometry, the researchers identified PPM1G, the host protein phosphatase, that interacts with ORF33. In in-body phosphatase experiments, the purified PPM1G of primary nucleation can directly dephosphate STING and MAVS, and ORF33 can enhance the interaction between PPM1G and STING or MAVS. These results show that ORF33 inhibits the activation of STING and MAVS by recruiting the host protein pphosphatase PPM1G to dephosphorylation. Further studies have found that PPM1G inhibits the host's IFN beta response, and that knocking down and knocking out the expression of PP1MG enhances the host's defenses against DNA and RNA viruses. These show that PPM1G is able to negatively regulate the host's natural antiviral immune response.
, the study first found that the protein phosphatase PPM1G is the host factor of negative regulation of natural antiviral immune response, and revealed a new strategy of herpes virus immune escape, namely, interstitial protein ORF33 recruits the host protein phosphatase PPM1G, dephosphorylation of STING and MAVS, thereby inhibiting the production of IFN beta and the host's antiviral response, which is conducive to virus replication.
research results on PPM1G restricts innate immune signaling mediated by STING and MAVS and is hijacked by KSHV for immune, on Science Advances. Deng Hongyu is the author of the thesis newsletter, Dr. Yu Fast of Deng Hongyu Group is the first author of the thesis, and Assistant Researcher Tian Huabin participated in the study. The research work is supported by the National Natural Science Foundation of China, the Ministry of Science and
, etc. (Source: China Institute
Biophysics)
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