Viral lncRNA: A regulatory molecule for controlling virus life cycle

Wang, Ziqiang; Zhao, Yiwan; Zhang, Yaou

In addition to functioning as a small ncRNA precursor, growing evidence has demonstrated that lncRNAs may function as "miRNA sponges" with diverse and far-reaching effects. HULC, which is a highly up-regulated lncRNA in liver cancer, contains a motif with a sequence targeted by miR-372. HULC has been reported to initiate a cascade of molecular events to increase chromatin accessibility for general transcription by recruiting miR-372 and attenuating its chromatin modification activity [76] . Recently, Wang et al. illustrated that the lncRNA linc-RoR functioned as a key competing endogenous RNA by preventing core transcription factors (TFs) from functioning in miRNA-mediated suppression and maintaining embryonic stem cell self-renewal and differentiation by targeting and antagonizing miR-145, which is a repressor of the translation of the core TF mRNAs [77] . To investigate the regulatory interactions between RNA classes, the interaction network between lncRNAs, miRNAs and mRNAs has been well-characterized computationally and experimentally [78, 79] . Systematic transcriptome-wide analysis of the multiple classes of RNAs suggests widespread regulatory roles for lncRNAs and indicates the potential ability of lncRNAs to act as important mediators of various biological processes. Through deep-sequencing technology, lncRNAs have been reported to play crucial roles in viral infection processes. Moreover, lncRNAs may act as a "bridge" that interlinks two types of viruses. For instance, in human parvovirus B19 (B19V)-infected cells, the adenoviral VA I RNA stimulates B19V capsid protein expression most likely by inhibiting the dsRNA-induced activation of PKR through competition for the PKR RNA-binding domain [80] . In HIV subtype E-infected pediatric patients, EBERs are co-expressed with the HIV core protein p24, which plays an important role in the interaction with host proteins during HIV-1 adsorption, membrane fusion, and entry, in surgical lung biopsies [81] . Therefore, lncRNAs may be a better target for viral intervention strategies due to their active regulatory roles in facilitating the host environment for viruses. A study reported that the ribosomal protein L22 might be able to buffer cells against the ability of EBER-1 to induce cellular transformation and impart resistance to the antiviral immune response by competitively binding EBER-1 [82] . High-level expression of viral EBER-1 can lead to the resistance of cells to physiological stresses and pro-apoptotic stimuli and can confer aspects of the transformed phenotype, resulting in outright tumorigenicity in some cases [46, 83] Moreover, the COX-2 inhibitor etodolac induced apoptosis via a Bcl-2-regulated pathway through inhibition of EBER expression [84] . These findings indicated the potential usefulness of lncRNAs as targets for viral intervention strategies, which could have therapeutic implications for the application of clinical approaches for the treatment of viral diseases. Currently, many gene therapeutic approaches in clinical trials are promising, such as small interfering RNAs, antisense oligonucleotides, ribozymes, etc. However, the major drawback of these approaches is that their function lacks persistence. Recently, the clustered regularly interspaced short palindromic repeats (CRISPR)-Cas9 system have the advantage of affecting interested gene permanently [85] and many viruses has been proven to be sensitive to this system [86e91]. Therefore, targeting lncRNA involved