Lysine residues of interferon regulatory factor 7 affect the replication and transcription activator-mediated lytic replication of Kaposi's sarcoma-associated herpesvirus/human herpesvirus 8

Abstract

Kaposi's sarcoma-associated herpesvirus (KSHV) infection goes through latent and lytic phases, which are controlled by the viral replication and transcription activator (RTA). Upon KSHV infection, the host responds by suppressing RTA-activated lytic gene expression through interferon regulatory factor 7 (IRF-7), a key regulator of host innate immune response. Lysine residues are potential sites for post-translational modification of IRF-7, and were suggested to be critical for its activity. In this study, we analysed the 15 lysine residues for their effects on IRF-7 function by site-directed mutagenesis. We found that some mutations affect the ability of IRF-7 to activate interferon (IFN)-α1 and IFN-β promoters, to suppress RTA-mediated lytic gene expression and to repress KSHV reactivation and lytic replication. However, other mutations affect only a subset of these four functions. These findings demonstrate that the lysine residues of IRF-7 play important roles in mediating IFN synthesis and modulating viral lytic replication.

Kaposi's Sarcoma-Associated Herpesvirus Noncoding Polyadenylated Nuclear RNA Interacts with Virus- and Host Cell-Encoded Proteins and Suppresses Expression of Genes Involved in Immune Modulation

“…PAN RNA accumulation in KSHV-infected cells is extremely high, so we predict that it has other functions and an even more pronounced effect on gene regulation than that observed in our expression cell lines. Immune response suppression by KSHV has been shown previously and involves various virus-encoded proteins (1,5,14,17,22,23,47). Interestingly, PAN RNA expression also resulted in a knockdown of expression of RNase L. Other viruses have evolved mechanisms to neutralize the function of RNase L during virus infection (12,39,40).…”

IRF7: activation, regulation, modification and function

“…However, mutation of K406 to R406 did not abolish IRF7 sumoylation promoted by Ebola Zaire virus VP35 protein, indicating that there are other potential sumoylation site(s), one of which is K43 (corresponding to human IRF7A K45), 102 and human IRF7A(K45R) can barely activate IFN promoter constructs. 161 In contrast to K63-linked ubiquitination that promotes IRF7 activation, sumoylation negatively regulates the transcriptional activity of IRF7 and -3 (ref. 160).…”

Transcriptome sequencing of neurologic diseases associated genes in HHV-6A infected human astrocyte

“…High basal ISG12a may inhibit NDV replication and oncolysis [34]. ISG15 inhibits the replication of influenza A virus [35] and the Japanese encephalitis virus [36] and controls the proinflammatory response against viral infection [37]. The consecutive study of these genes in astrocytes can provide new clue for the elucidating of viral antagonism in HHV-6A infection.…”