Long Non-Coding RNAs: Novel Players in Regulation of Immune Response Upon Herpesvirus Infection

Abstract

Herpesviruses have developed a variety of sophisticated immune evasion strategies to establish lifelong latent infection, including the use of long non-coding RNAs (lncRNAs). In this review, we summarize the lncRNA action modes, i.e., RNA-protein, RNA-RNA, and RNA-DNA interactions, involved in regulating important aspects of immunity by controlling gene expression at various stages. Upon herpesvirus infection, host lncRNAs, such as nuclear paraspeckle assembly transcript 1, negative regulator of antiviral, and B-cell integration cluster have been functionally characterized as negative or positive antiviral regulators in the immune response. Herpesviruses have also evolved multiple strategies to modulate the host immune response using lncRNAs, such as latency-associated transcript, β 2.7 RNA, 5 kb and 7.2 kb lncRNAs, Epstein-Barr virus-encoded non-coding RNA, BamH I-A rightward transcripts, polyadenylated nuclear, and herpesvirus saimiri U-rich RNAs. We discuss the various mechanisms of immune-related lncRNAs, and their diversified and important functions in the modulation of innate and adaptive immunity upon herpesvirus infection as well as in host-pathogen interactions, which will facilitate our understanding of rational design of novel strategies to combat herpesvirus infection.

Keywords: adaptive immunity; herpesvirus; host–pathogen interaction; innate immunity; long non-coding RNAs; virus infection.

Figure 1

Mechanism employed by long non-coding RNA (lncRNA) in immune regulation. (A) Loci of immune-related lncRNAs relative to protein-coding genes. In general, immune-related lncRNAs are transcribed by RNAP II and classified relative to the position of the neighboring protein-coding gene into different types, including intronic lncRNA, long intergenic ncRNA (lincRNA), enhancer RNA (eRNA), and antisense lncRNA. (B) Mechanisms employed by lncRNAs. lncRNAs use a variety of basic modules to perform their regulatory functions in the cytosol and nucleus through lncRNA–protein, lncRNA–RNA, and lncRNA–DNA interactions. (C) Function of herpesviruses’ lncRNAs in immune regulation. The Kaposi’s sarcoma-associated herpesvirus (KSHV)-encoded lncRNA polyadenylated nuclear (PAN) binds the histone-modifying complex (demethylases JMJD3 and UTX) which plays an important role in the switch from latent to lytic infection. PAN also subverts the host immune response and modulates viral gene expression through binding with PRC2 to promote cell growth and survival, and to repress the inflammatory response. Nuclear paraspeckle assembly transcript 1 (NEAT1) binds several proteins such as SFPQ, and plays a critical role in regulation of the innate immune response mechanism through the transcriptional regulation of numerous antiviral genes upon herpesvirus infection.

Figure 2

Long non-coding RNA (lncRNA) in regulation of the innate and adaptive immune system upon herpesvirus infection. Many lncRNAs have been associated with regulation of the innate and adaptive immune response and host–pathogen interactions, including nuclear paraspeckle assembly transcript 1 (NEAT1), negative regulator of antiviral (NRAV), polyadenylated nuclear (PAN), Epstein–Barr virus-encoded non-coding RNAs (EBERs), herpesvirus saimiri U-rich RNAs (HSURs), β 2.7 RNA, and latency-associated transcript (LAT).