Histone H2A Nuclear/Cytoplasmic Trafficking Is Essential for Negative Regulation of Antiviral Immune Response and Lysosomal Degradation of TBK1 and IRF3

Abstract

Histone H2A is a nuclear molecule tightly associated in the form of the nucleosome. Our previous studies have demonstrated the antibacterial property of piscine H2A variants against gram-negative bacteria Edwardsiella piscicida and Gram-positive bacteria Streptococcus agalactiae. In this study, we show the function and mechanism of piscine H2A in the negative regulation of RLR signaling pathway and host innate immune response against spring viremia of carp virus (SVCV) infection. SVCV infection significantly inhibits the expression of histone H2A during an early stage of infection, but induces the expression of histone H2A during the late stage of infection such as at 48 and 72 hpi. Under normal physiological conditions, histone H2A is nuclear-localized. However, SVCV infection promotes the migration of histone H2A from the nucleus to the cytoplasm. The in vivo studies revealed that histone H2A overexpression led to the increased expression of SVCV gene and decreased survival rate. The overexpression of histone H2A also significantly impaired the expression levels of those genes involved in RLR antiviral signaling pathway. Furthermore, histone H2A targeted TBK1 and IRF3 to promote their protein degradation via the lysosomal pathway and impair the formation of TBK1-IRF3 functional complex. Importantly, histone H2A completely abolished TBK1-mediated antiviral activity and enormously impaired the protein expression of IRF3, especially nuclear IRF3. Further analysis demonstrated that the inhibition of histone H2A nuclear/cytoplasmic trafficking could relieve the protein degradation of TBK1 and IRF3, and blocked the negative regulation of histone H2A on the SVCV infection. Collectively, our results suggest that histone H2A nuclear/cytoplasmic trafficking is essential for negative regulation of RLR signaling pathway and antiviral immune response in response to SVCV infection.

Mutation in the FUS nuclear localisation signal domain causes neurodevelopmental and systemic metabolic alterations

“…Interestingly, the histone H1.2 has been found translocated into the cytoplasm upon an apoptotic stimulus, such as DNA damage, where it initiates the permeabilisation of the mitochondria and apoptosis ( Konishi et al, 2003 ). Recently, nuclear-cytoplasmic trafficking of the histone H1.2 has been found to be essential in the regulation of TBK1 and IRF3 inflammation and antiviral activity ( Wu et al, 2021a ). TBK1 is another gene that causes ALS and FTD, and the TBK1 and FUS pathways might represent converging pathological pathways in disease ( Gurfinkel et al, 2022 ).…”

FUSDelta14 mutation impairs normal brain development and causes systemic metabolic alterations

“…Interestingly, the histone H1.2 has been found translocated into the cytoplasm upon an apoptotic stimulus, such as DNA damage, where it initiates the permeabilization of the mitochondria and apoptosis (42). Recently, nuclear-cytoplasmic trafficking of the histone H1.2 has been found to be essential in the regulation of the TBK1 and IRF3 inflammation and antiviral activity (43). TBK1 is another gene that causes ALS and FTD, which might represent a converging pathological pathway in disease (44).…”