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View metadata, citation and similar papers at core.ac.uk brought to you by CORE provided by Springer - Publisher Connector Retrovirology BioMed Central Review Open Access Host-virus interaction: a new role for microRNAs Vinod Scaria, Manoj Hariharan, Souvik Maiti, Beena Pillai and Samir K Brahmachari* Address: GN Ramachandran Knowledge Center for Genome Informatics, Institute of Genomics and Integrative Biology, CSIR, Mall Road, Delhi 110 007, India Email: Vinod Scaria - [email protected]; Manoj Hariharan - [email protected]; Souvik Maiti - [email protected]; Beena Pillai - [email protected]; Samir K Brahmachari* - [email protected] * Corresponding author Published: 11 October 2006 Received: 30 August 2006 Accepted: 11 October 2006 Retrovirology 2006, 3:68 doi:10.1186/1742-4690-3-68 This article is available from: http://www.retrovirology.com/content/3/1/68 © 2006 Scaria et al; licensee BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. Abstract MicroRNAs (miRNAs) are a new class of 18–23 nucleotide long non-coding RNAs that play critical roles in a wide spectrum of biological processes. Recent reports also throw light into the role of microRNAs as critical effectors in the intricate host-pathogen interaction networks. Evidence suggests that both virus and hosts encode microRNAs. The exclusive dependence of viruses on the host cellular machinery for their propagation and survival also make them highly susceptible to the vagaries of the cellular environment like small RNA mediated interference. It also gives the virus an opportunity to fight and/or modulate the host to suite its needs. Thus the range of interactions possible through miRNA-mRNA cross-talk at the host-pathogen interface is large. These interactions can be further fine-tuned in the host by changes in gene expression, mutations and polymorphisms. In the pathogen, the high rate of mutations adds to the complexity of the interaction network. Though evidence regarding microRNA mediated cross-talk in viral infections is just emerging, it offers an immense opportunity not only to understand the intricacies of host- pathogen interactions, and possible explanations to viral tropism, latency and oncogenesis, but also to develop novel biomarkers and therapeutics. Background of cellular proteins – what is commonly termed as the MicroRNAs (miRNAs) are small RNA molecules which RNA Induced Silencing Complex (RISC). have recently gained widespread attention as critical regu- lators in complex gene regulatory networks in eukaryotes. MicroRNA mediated regulation has been lately shown to These small RNA, processed from non-coding regions of encompass a wide spectrum of host biological processes the genome into 18–23 nucleotide long single stranded ranging from growth and development to oncogenesis [2- RNA, have been shown to regulate translation of messen- 5]. Recent genome-wide computational screens for micro- ger RNA (mRNA) by binding to it and effecting target RNA targets in humans predict that 10% [6] to 30% [7] of cleavage or translational block depending on the extent of all genes are regulated by microRNAs. The regulatory net- sequence complementarity with the target [1]. Generally, work of miRNA-mRNA interaction is rendered even more in mammalian systems, microRNAs bind to targets with complex because of multiplicity and cooperativity of incomplete complementarity, in association with a host microRNA targeting. Page 1 of 9 (page number not for citation purposes) Retrovirology 2006, 3:68 http://www.retrovirology.com/content/3/1/68 MicroRNAs have recently been implicated in the intricate composes of miRNA and its complementary strand cross-talk between the host and the pathogen [8] in viral miRNA*) to be associated with the RNA Induced Silenc- infections and is thought to play a major role in viral ing Complex (RISC). pathogenesis. Though studies into the entire spectrum of host-pathogen interactions at the microRNA level are still Mechanisms of action in its infancy, there has been a recent spurt in reports The mechanism of action of microRNAs is considered to exploring the possibility in a number of major pathogenic be by two modes – translational repression and target deg- viruses of humans. radation. The former is common in mammalian systems while the latter is found predominantly in plants. The MicroRNAs were initially discovered in 1993, in a genetic basic difference in the two mechanisms is thought to be screen for mutants that disrupt the timing of post-embry- primarily governed by the levels of complementarity onic development in the nematode Caenorhabditis elegans between microRNAs and their target transcripts. Perfect or [9], and were thought to be an oddity in gene regulation, near perfect complementarity as is common in plant of nematodes till 2000. About 7 years later, when let7 was microRNAs and in a small class of eukaryotic microRNAs discovered [10], and was found to be highly conserved in causes target cleavage and degradation [14], analogous to eukaryotes, it led to a surge in discovery of new microR- the action of siRNAs which have perfect complementarity NAs in a number of organisms including humans. to the target regions. Evidence suggests that microRNA bound transcripts are sequestrated into P bodies [15,16] Biogenesis and mechanism of action of where they are maintained in a silenced state either by microRNAs associating with proteins that prevent translation or pos- MicroRNA gene location sibly by removal of the cap structure [16]. MicroRNAs have been classically thought to be tran- scribed from intergenic regions, but recent large-scale In fact, one microRNA can have binding sites in multiple genome-wide cloning experiments [11] have shown that targets (in humans, this comes to hundreds) and one tar- microRNAs can be derived from introns as well. Intergenic get can be repressed by multiple microRNAs (multiplicity microRNAs are sometimes found to occur as clusters and co-operativity) [6]. Moreover, the target repression is which would be transcribed as polycistronic transcripts likely to be dosage dependent, adding to the complexity and are shown to share similar expression profiles [12]. A of the network of genetic regulation. Recent evidence also significant proportion of microRNAs are encoded within suggests an overdose of artificial short hairpin RNAs (shR- the introns of protein-coding genes, presumably NAs) can saturate the RNA interference machinery [17]. expressed in sync with them. A few microRNAs have been This would have far reaching implications on determining mapped to the exons of protein-coding genes. One exam- dosage of artificial microRNAs for therapeutics as well as ple is hsa-mir-20a which is annotated by miRBase to arise for experimental research. The biogenesis and action is from the exon 2 as well as introns 5 and 8 of alternative summarized in Figure 1. transcripts of C13orf25. The significance of these microR- NAs and their roles in alternatively spliced transcripts are Non-classical mechanisms of action yet to be addressed. Recent evidence suggests that microRNAs can also regu- late protein expression through non-classical ways. Maturation Genome-wide expression analysis of microRNA targets MicroRNAs are transcribed by RNA Polymerase II as pri- have shown to decrease the transcript levels [18]. But mary microRNAs (pri-miRNAs) which range from hun- whether this is a direct or indirect effect is yet to be dreds to thousands of nucleotides in length and resemble explored. A couple of recent reports also suggest that protein-coding transcripts in that they are poly-ade- microRNAs can modulate de-adenylation of transcripts nylated and capped [1]. These pri-miRNAs are then proc- [19,20]. MicroRNAs are classically thought to be negative essed by nuclear localized enzymes Drosha or Pasha regulators, but with exceptions as in the case of a reported (DGCR8 in humans) to produce thermodynamically sta- human microRNA which can cause abundance of Hepati- ble hairpin structures known as pre-microRNAs (pre-miR- tis RNA [21] (vide infra). A recent report by Bhattacharyya NAs), of ~70 bases. These pre-microRNAs are then et al suggests that microRNA mediated mechanism of exported to the cytoplasm by Exportin-5 and are then fur- post-transcriptional repression of gene expression is ther processed by the RNAase III enzyme Dicer, to form indeed reversible [22], suggesting that the proteins associ- duplexes of 18–23 bases. This duplex is unwound by a yet ated with microRNA-mRNA complex modulate the to be discovered helicase. In steps shared with the siRNA expression of the transcript in a switch-like mechanism, (small interfering RNA) pathway the strand with lower responding to particular stimuli. This mechanism, if stability in the 5' end (guide strand) is preferentially proved to be a generalized phenomenon, would have selected [13] from the double stranded molecule (which large implications in the regulation of gene expression in Page 2 of 9 (page number not for citation purposes) Retrovirology 2006, 3:68 http://www.retrovirology.com/content/3/1/68 SchematicFigure 1 overview of biogenesis and action of microRNAs in eukaryotic cells Schematic overview of biogenesis and action of microRNAs in eukaryotic cells. relation to particular stimuli. In summary microRNAs can structural components of precursor hairpins involved in act as a trans-acting element for reversible and dynamic microRNA biogenesis [26]. We have recently developed a regulation of spatial and temporal protein expression. de novo method (unpublished results) for microRNA pre- diction in viruses based on Support Vector Machines, Computational tools for discovery of microRNA rationalizing that virus encoded microRNA precursor and their targets hairpins would share the sequence and structure features Computational predictions have been the mainstay for with that of host as they share the same microRNA discovery of microRNAs and their targets. The algorithms processing machinery.