Stealing the Show: KSHV Hijacks Host RNA Regulatory Pathways to Promote Infection

Abstract

Kaposi’s sarcoma-associated herpesvirus (KSHV) induces life-long infections and has evolved many ways to exert extensive control over its host’s transcriptional and post-transcriptional machinery to gain better access to resources and dampened immune sensing. The hallmark of this takeover is how KSHV reshapes RNA fate both to control expression of its own gene but also that of its host. From the nucleus to the cytoplasm, control of RNA expression, localization, and decay is a process that is carefully tuned by a multitude of factors and that can adapt or react to rapid changes in the environment. Intriguingly, it appears that KSHV has found ways to co-opt each of these pathways for its own benefit. Here we provide a comprehensive review of recent work in this area and in particular recent advances on the post-transcriptional modifications front. Overall, this review highlights the myriad of ways KSHV uses to control RNA fate and gathers novel insights gained from the past decade of research at the interface of RNA biology and the field of KSHV research.

Transcriptome-wide N6-methyladenosine modification profiling of long non-coding RNAs during replication of Marek’s disease virus in vitro

“…Moreover, mutations in AIV transcripts to alleviate m 6 A modifications reduced viral pathogenicity thereby confirming this important regulatory role. Thus overall, there is evidence that up-regulation of m 6 A modified transcripts might be a common feature for both DNA and RNA viruses that helps facilitate viral replication through regulating host RNA regulatory pathways [ 27 ].…”

A non-coding RNA network involved in KSHV tumorigenesis

“…Before RNAs can interact with nuclear export machinery, they must undergo processes that regulate the number of transcripts that is exported to the cytoplasm or nuclear decay pathways. KSHV manipulation of nuclear RNA regulation is one of the strategies acquired by the virus to influence the host RNAs during viral infection [Macveigh-Fierro et al, 2020]. In fact, it was very recently demonstrated that NMD pathway targets KSHV RNAs to restrict the virus [Zhao et al, 2020].…”

“…At this stage, KSHV is particularly effective at exploiting host gene expression for its own benefit. In this sense, the coevolution of the virus and its host has developed an intricate association between the virus genome, with its coding genes and non-coding genes, and the host RNA biosynthesis machinery [Macveigh et al, 2020]. To the point that KSHV can seize control of RNA surveillance pathways, such as DNA damage response (DDR), pre-mRNA control machinery and the Nonsense-mediated mRNA decay (NMD), to fine-tuningthe global gene expression environment throughout both phases of infection [Yan et al, 2019, Ohsaki et al, 2020, Zhao et al, 2020].…”

CRISPR Interference Efficiently Silences Latent and Lytic Viral Genes in Kaposi’s Sarcoma-Associated Herpesvirus-Infected Cells

“…KSHV has a large, circular dsDNA genome of 160–170 Kb, which encodes over 90 open reading frames (ORFs), more than two dozen short ORFs and upstream ORFs, circular RNAs, several long noncoding RNAs (ncRNAs), and 25 micro RNAs [ 5 , 6 ]. Functional genomics studies have revealed the role of several viral ORFs and ncRNAs in immunomodulation [ 7 ], oncogenesis [ 3 , 8 ], and the basic biology of the abduction of the cellular machinery by the virus [ 9 , 10 , 11 , 12 , 13 ]. Nevertheless, several viral elements’ biological roles, including long ncRNAs and alternative transcripts, remain unclear.…”