Mechanism Research Of Histone Demethylase LSD1 Regulating Innate Immunity RIG-I Signaling Pathway

Innate immunity is an important line of defense against pathogens.Pattern recognition theory,that pattern recognition receptors（PRRs）recognize pattern-associated molecular patterns（PAMPs）,is one widely accepted model for the fields of innate immunity.RIG-I,serving as a PRR,can recognize cytoplasm viral RNA generated by single-strand or double-strand RNA virus.With subsequent ubiquitination and oligomerization,RIG-I signaling pathway is activated and induces type I interferon to repress exogenous virus.We utilized a si RNA library to screen epigenetic enzymes for regulator of RIG-I signaling pathway.Then we found that LSD1 depletion impaired Se V-induced cellular IFNB1 expression.Further validation indicated that LSD1 knockdown in 293T cell decreased the expression of IFNB1,ISG54,ISG56,as well as the phosphorylation of TBK1 and IRF3,the hallmarks of RIG-I pathway activation,while overexpression of LSD1 in 293T caused the opposite.Further mechanistic study showed that LSD1 exerts its regulatory role in RIG-I pathway not dependent on its demethylase activity;it interacts with RIG-I,promotes the interaction between RIG-I and its E3 ligase TRIM25,and thus promotes RIG-I’s K63-linked ubiquitination and subsequent downstream activation.To further prove it in vivo,We generated macrophage-specific knockdown mice from Lyz2-Cre mice and Lsd1^fl/+Mice.We validated the above Lsd1’s function of regulating anti-RNA-virus response in primary cells and in vivo.We confirmed that Lsd1is also essential for the activation of antiviral genes in the animal model.To sum up,we reveal the novel function of LSD1 as a positive regulator of RIG-I pathway,and confirm the molecular mechanism independent of its demethylase activity,which provides a new potential therapeutic target of innate immunity associated disease.