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
ABSTRACT 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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- "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. "
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.Frontiers in Molecular Neuroscience 02/2014; 7:9. DOI:10.3389/fnmol.2014.00009 · 4.08 Impact Factor
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ABSTRACT: Kaposi's sarcoma-associated herpesvirus (KSHV), also called human herpesvirus 8, belongs to the gamma herpesviruses and is the etiological agent of Kaposi's sarcoma, primary effusion lymphoma, and some types of multicentric Castleman's disease. In vivo, KSHV mainly infects B cells and endothelial cells. The interactions between KSHV and its host cells determine the outcome of viral infection and subsequent viral pathogenesis. MicroRNAs (miRNAs) are small, non-coding RNAs that are important in fine-tuning cellular signaling. During infection, KSHV modulates the expression profiles and/or functions of a number of host miRNAs, for example hsa-miR-132 and hsa-miR-146a. Meanwhile, KSHV itself encodes 12 pre-miRNAs, including miR-K12-11, which is the functional ortholog of the host miR-155. A number of cellular and viral targets of deregulated cellular miRNAs and viral miRNAs are found in KSHV-infected cells, which suggests that miRNAs may be important in mediating KSHV-host interactions. In this review, we summarize our current understanding of how KSHV modulates the expression and/or functions of host miRNAs; we review in detail the functions of miR-K12-11 as the ortholog of miR-155; and we examine the functions of viral miRNAs in KSHV life cycle control, immune evasion, and pathogenesis.Frontiers in Microbiology 01/2011; 2:271. DOI:10.3389/fmicb.2011.00271 · 3.94 Impact Factor
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ABSTRACT: The farnesoid X receptor (FXR) is a member of the nuclear receptor superfamily that is highly expressed in liver, kidney, adrenal gland, and intestine. It plays an important role in regulating the progression of several cancers including hepatocellular carcinoma (HCC). So it is necessary to study the regulation of FXR. In this study, we found that the expression of miR-421 was inversely correlated with FXR protein level in HCC cell lines. Treatment with miR-421 mimic repressed FXR translation. The reporter assay revealed that miR-421 targeted 3' untranslated region of human FXR mRNA. Furthermore, downregulation of FXR by miR-421 promoted the proliferation, migration, and invasion of HCC cells. These results suggest that miR-421 may serve as a novel molecular target for manipulating FXR expression in hepatocyte and for the treatment of HCC.Molecular Cancer Research 03/2012; 10(4):516-22. DOI:10.1158/1541-7786.MCR-11-0473 · 4.50 Impact Factor