Human cytomegalovirus induces and exploits Roquin to counteract the IRF1-mediated antiviral state

Abstract

RNA represents a pivotal component of host–pathogen interactions. Human cytomegalovirus (HCMV) infection causes extensive alteration in host RNA metabolism, but the functional relationship between the virus and cellular RNA processing remains largely unknown. Through loss-of-function screening, we show that HCMV requires multiple RNA-processing machineries for efficient viral lytic production. In particular, the cellular RNA-binding protein Roquin, whose expression is actively stimulated by HCMV, plays an essential role in inhibiting the innate immune response. Transcriptome profiling revealed Roquin-dependent global down-regulation of proinflammatory cytokines and antiviral genes in HCMV-infected cells. Furthermore, using cross-linking immunoprecipitation (CLIP)-sequencing (seq), we identified IFN regulatory factor 1 (IRF1), a master transcriptional activator of immune responses, as a Roquin target gene. Roquin reduces IRF1 expression by directly binding to its mRNA, thereby enabling suppression of a variety of antiviral genes. This study demonstrates how HCMV exploits host RNA-binding protein to prevent a cellular antiviral response and offers mechanistic insight into the potential development of CMV therapeutics.

Interferon regulatory factor 1 (IRF1) and anti-pathogen innate immune responses

“…Alternatively, viruses can usurp cellular components to downregulate IRF1 expression and thus inhibit IRF1-mediated innate immune responses. For instance, human cytomegalovirus (HCMV) has recently been shown to induce the expression of roquin, an RNA-binding protein that interacts with a stem-loop in the 5’ untranslated region (5’UTR) of IRF1 transcripts to inhibit their translation [ 93 ].…”

An eIF3d-dependent switch regulates HCMV replication by remodeling the infected cell translation landscape to mimic chronic ER stress

“…Representative HCMV IE (IE1/2) and E (UL44) protein accumulation was inhibited to a much greater extent by depleting eIF3 subunits a, b, or g compared to eIF3d or e ( Figure 3B , compare lanes 1, 6, 7, 8 to lanes 2, 3, 4, 5, 9, 10), whereas L protein pp28 accumulation was reduced substantially by depleting human eIF3 functional core (a, b, e) or non-core (d, g) subunits ( Figure 3B ). Besides interfering with virus protein accumulation, depletion of eIF3a or e reduced infectious virus production ( Figure S4 ), as did depletion of eIF3b or g ( Figure S4 ) ( Song et al, 2019 ). The requirement of human eIF3 functional core subunits for HCMV protein accumulation and replication is not surprising, given their essential role loading 40S ribosomes on host and virus mRNAs during canonical and non-canonical cap-dependent translation initiation, respectively reliant upon eIF4E and eIF3d ( Cate, 2017 ; Lee et al, 2015 , 2016 ).…”

Tuning the Orchestra: HCMV vs. Innate Immunity

“…This is however a controversial point, as a more recent study has shown that HCMV, instead of taking part in the entry process, exploits IFITMs at later time points of its viral cycle to facilitate the formation of the virion assembly compartment (vAC), which enhances virion assembly (Xie et al, 2015). Finally, a very recent work elegantly described the ability of HCMV to actively stimulate the cellular RNA-binding protein Roquin in inhibiting the innate immune response through the suppression of IRF1 antiviral activity (Song et al, 2019).…”