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Figure caption: Regulatory function of DUSP4 in STING- and RIG-I-mediated type I interferon responses. In innate immune cells such as macrophages, cytosolic RNA and DNA from microbial pathogens are detected by RIG-I and cGAS respectively, which lead to the activation of TBK1-IRF3 and ERK for the transcription of IFNβ. Meanwhile, microbial pathogen infection increased the expression of DUSP4 which is recruited into a signalling complex including TBK1, ERK and IRF3. DUSP4 dephosphorylates TBK1 and ERK thereby downregulating the activation of IRF3 and AP1 to negatively regulate IFNβ expression.
DUSP4 modulates RIG-I- and STING-mediated IRF3-type I IFN response
Detection of cytosolic nucleic acids by pattern recognition receptors, including STING and RIG-I, leads to the activation of multiple signalling pathways that culminate in the production of type I interferons (IFNs) which are vital for host survival during virus infection. In addition to protective immune modulatory functions, type I IFNs are also associated with autoimmune diseases. Hence, it is important to elucidate the mechanisms that govern their expression. In this study, we identified a critical regulatory function of the DUSP4 phosphatase in innate immune signalling. We found that DUSP4 regulates the activation of TBK1 and ERK1/2 in a signalling complex containing DUSP4, TBK1, ERK1/2 and IRF3 to regulate the production of type I IFNs. Mice deficient in DUSP4 were more resistant to infections by both RNA and DNA viruses but more susceptible to malaria parasites. Therefore, our study establishes DUSP4 as a regulator of nucleic acid sensor signalling and sheds light on an important facet of the type I IFN regulatory system.
Jiao H, James SJ, CW P,...Zhang YL. DUSP4 modulates RIG-I- and STING-mediated IRF3-type I IFN response. Cell Death Differ. 31, 280–291 (2024). https://doi.org/10.1038/s41418-024-01269-7.