Recently, Prof. Gao Chengjiang's team from the School of Basic Medical Sciences of Shandong University has made new contribution in the field of innate immune regulation, and published a research paper entitled "USP18 positively regulates innate antiviral immunity by promoting K63-linked polyubiquitination of MAVS" in Nature Communications(five years’ IF=13.611).Prof. Gao Chengjiang and assistant researcher Zheng Yi are the co-corresponding authors of this paper. PhD candidate Hou Jinxiu is the first author. This research was supported by Prof. Yi Fan and Prof. Ma Chunhong. Shandong University is the first author institute and the sole corresponding author institute.
The Pathogen Associated Molecular Patterns (PAMPs), such as viral nucleic acids, can be detected by the Pattern Recognition Receptors (PRRs) of the host cell. This interaction between viral PAMPs and cellular PRRs elicits an elegant innate immune signaling transduction. The sensing of viral RNA by RLRs results in their activation and subsequent interaction with the adaptor protein mitochondrial antiviral signaling protein (MAVS). A series of studies have emphasized the importance of posttranslational modification (PTM) in modulating the activity of MAVS, especially the ubiquitination of MAVS. An early study of Prof. Gao Chengjiang's team published in the top international journal of immunologyNature Immunology（2017, 18:214-224）observed that TRIM31 is enriched in mitochondria upon viral infection, facilitating the K63-linked polyubiquitination and subsequent aggregation of MAVS, initiating downstream antiviral type I interferon response.TRIM31 is the only E3 ligase specifically regulating K63-linked polyubiquitination of MAVS, but the mechanism by which TRIM31 localizes to the mitochondria is unclear.
We observe that USP18 can significantly promote the polyubiquitination of MAVS by screening 13 DUBs likely distributed in mitochondria. In a further study, USP18 is enriched in mitochondria and have enhanced interaction with MAVS following RNA viral infection, suggesting the possible regulation of MAVS activity by USP18. Furthermore, USP18 facilitates the K63-linked polyubiquitination and subsequent aggregation of MAVS. Consequently, the deletion of USP18 in macrophages or fibroblasts leads to impaired type I interferon response following viral infection. More importantly, mice with a deficiency of USP18 are more susceptible to viral infection. Mechanistically, the effect of USP18 on MAVS is independent of its enzymatic activity but dependent on TRIM31. Upon viral infection, USP18 is critical for the re-localization of TRIM31 from the cytoplasm to mitochondria and the interaction between TRIM31 and MAVS, demonstrating that TRIM31 is an important molecule for RNA virus infection to activate host innate immunity, which requires fine multi-level regulation.
Prof. Gao Chengjiang is currently the deputy editor-in-chief of "Molecular Immunology", the editorial board of "Cellular and Molecular Immunology", and the director of Shandong Provincial Key Laboratory of Infection and Immunology. He has been committed to the research on the regulation mechanism of innate immune signal transduction for a long time. The research results are published in Nat Immunol, J Exp Med, Nat Commun, Plos Pathog and other international authoritative academic journals of immunology and virology. This research is supported by the National Natural Science Foundation of China, the key projects of the National Natural Science Foundation of China, the Outstanding Youth Fund, and the Shandong University Climbing Project Innovation Team.
Link to the article:https://doi.org/10.1021/acscatal.0c05378