Kaposi's sarcoma-associated herpesviral IL-6 and human IL-6 open reading frames contain miRNA binding sites and are subject to cellular miRNA regulation

HIV and AIDS Malignancy Branch, Center for Cancer Research, National Cancer Institute, NIH, Bethesda, MD 20892, USA.
The Journal of Pathology (Impact Factor: 7.43). 11/2011; 225(3):378-89. DOI: 10.1002/path.2962
Source: PubMed


Kaposi's sarcoma-associated herpesvirus (KSHV) encodes a viral interleukin 6 (vIL-6) that mimics many activities of human IL-6 (hIL-6). Both vIL-6 and hIL-6 play important roles in stimulating the proliferation of tumours caused by KSHV. Here, we provide evidence that a miRNA pathway is involved in regulation of vIL-6 and hIL-6 expression through binding sites in their open reading frames (ORFs). We show a direct repression of vIL-6 by hsa-miR-1293 and hIL-6 by hsa-miR-608. The repression of vIL-6 by miR-1293 was reversed by disruption of the vIL-6 miR-1293 seed match through the introduction of point mutations. In addition, expression of vIL-6 or hIL-6 in KSHV-infected cells could be enhanced by transfection of the respective miRNA inhibitors. In situ hybridization of human lymph node sections revealed that miR-1293 is primarily expressed in the germinal centre but is deficient in the mantle zone of lymph nodes, where the expression of vIL-6 is often found in patients with KSHV-associated multicentric Castleman's disease, providing evidence of an anatomical correlation. Taking these factors together, our study indicates that IL-6 expression can be regulated by miRNA interactions in its ORF and provides evidence for the role of these interactions in the pathogenesis of KSHV-associated diseases.

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    • "For example, human liver-specific miR-122 has been shown to functionally augment the replication of hepatitis C virus (HCV) (Jopling et al., 2005), while miR-199a-3p, miR-210, and miR-125a-5p have been found to repress the replication of hepatitis B virus (HBV) (Liu et al., 2011). More recent data have suggested that herpes viruses (such as the Epstein–Barr virus [EBV] and Kaposi's sarcoma herpes virus [KSHV]) were targeted by several cellular miRNAs, including the miR-17/92 and miR-106b/25 clusters (Kang et al., 2011; Riley et al., 2012; Skalsky et al., 2012). MiR-21 is one of the earliest miRNAs to be discovered (Lagos- Quintana et al., 2001). "
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    Virology 05/2014; s 456–457(1):319–328. DOI:10.1016/j.virol.2014.03.032 · 3.32 Impact Factor
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    • "Predictably, miR-608 shows thousands of potential targets (miRNAwalk: Of those, the validated miR-608 targets Rho GTPase CDC42 (19) and IL6 (20) are predictably involved in anxiety and parasympathetic signaling. Bioinformatics analysis (RNAhybrid, "
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    ABSTRACT: MicroRNAs (miRNAs) can repress multiple targets, but how a single de-balanced interaction affects others remained unclear. We found that changing a single miRNA–target interaction can simultaneously affect multiple other miRNA–target interactions and modify physiological phenotype. We show that miR-608 targets acetylcholinesterase (AChE) and demonstrate weakened miR-608 interaction with the rs17228616 AChE allele having a single-nucleotide polymorphism (SNP) in the 3′-untranslated region (3′UTR). In cultured cells, this weakened interaction potentiated miR-608-mediated suppression of other targets, including CDC42 and interleukin-6 (IL6). Postmortem human cortices homozygote for the minor rs17228616 allele showed AChE elevation and CDC42/IL6 decreases compared with major allele homozygotes. Additionally, minor allele heterozygote and homozygote subjects showed reduced cortisol and elevated blood pressure, predicting risk of anxiety and hypertension. Parallel suppression of the conserved brain CDC42 activity by intracerebroventricular ML141 injection caused acute anxiety in mice. We demonstrate that SNPs in miRNA-binding regions could cause expanded downstream effects changing important biological pathways.
    Human Molecular Genetics 04/2014; 23(17). DOI:10.1093/hmg/ddu170 · 6.39 Impact Factor
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    • "Combined use of four different bioinformatics algorithms identified a large number of miRNAs putatively targeting the 3 UTRs of ChAT, VAChT, AChE-S, AChE-R, and BChE. MiRNAs can notably regulate whole biological pathways; for example, miR- 181 controls mouse hematopoiesis (Chen et al., 2004), miR-608 targets two inflammation-related transcripts, CDC42 and IL6 (Jeyapalan et al., 2011; Kang et al., 2011) and miR-221 controls multiple cancer pathways (Lupini et al., 2013). To challenge the possibility that certain miRNAs likewise regulate ACh metabolism and belong to the family of CholinomiRs, we searched for miR- NAs targeting more than one of the five transcripts involved in the process of ACh synthesis, packaging and degradation. "
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    ABSTRACT: MicroRNAs (miRNAs) can notably control many targets each and regulate entire cellular pathways, but whether miRNAs can regulate complete neurotransmission processes is largely unknown. Here, we report that miRNAs with complementary sequence motifs to the key genes involved in acetylcholine (ACh) synthesis and/or packaging show massive overlap with those regulating ACh degradation. To address this topic, we first searched for miRNAs that could target the 3'-untranslated regions of the choline acetyltransferase (ChAT) gene that controls ACh synthesis; the vesicular ACh transporter (VAChT), encoded from an intron in the ChAT gene and the ACh hydrolyzing genes acetyl- and/or butyrylcholinesterase (AChE, BChE). Intriguingly, we found that many of the miRNAs targeting these genes are primate-specific, and that changes in their levels associate with inflammation, anxiety, brain damage, cardiac, neurodegenerative, or pain-related syndromes. To validate the in vivo relevance of this dual interaction, we selected the evolutionarily conserved miR-186, which targets both the stress-inducible soluble "readthrough" variant AChE-R and the major peripheral cholinesterase BChE. We exposed mice to predator scent stress and searched for potential associations between consequent changes in their miR-186, AChE-R, and BChE levels. Both intestinal miR-186 as well as BChE and AChE-R activities were conspicuously elevated 1 week post-exposure, highlighting the previously unknown involvement of miR-186 and BChE in psychological stress responses. Overlapping miRNA regulation emerges from our findings as a recently evolved surveillance mechanism over cholinergic neurotransmission in health and disease; and the corresponding miRNA details and disease relevance may serve as a useful resource for studying the molecular mechanisms underlying this surveillance.
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