Abstract
In addition to modulating the function and stability of cellular mRNAs, microRNAs can profoundly affect the life cycles of viruses bearing sequence complementary targets, a finding recently exploited to ameliorate toxicities of vaccines and oncolytic viruses. To elucidate the mechanisms underlying microRNA-mediated antiviral activity, we modified the 3′ untranslated region (3′UTR) of Coxsackievirus A21 to incorporate targets with varying degrees of homology to endogenous microRNAs. We show that microRNAs can interrupt the picornavirus life-cycle at multiple levels, including catalytic degradation of the viral RNA genome, suppression of cap-independent mRNA translation, and interference with genome encapsidation. In addition, we have examined the extent to which endogenous microRNAs can suppress viral replication in vivo and how viruses can overcome this inhibition by microRNA saturation in mouse cancer models.
Highlights
MicroRNAs are a class of small,22 nt regulatory RNAs that modulate a diverse array of cellular activities
To investigate at what stage(s) of the viral life cycle cellular miRNAs are able to perturb viral replication, we utilized our previous recombinant miRNA target elements (miRTs) design whereby four tandem copies of a given target element corresponding to a cellular miRNA are incorporated into the 39 untranslated region (39UTR) of the viral genome (Figure 1A)
Target elements corresponding to muscle-specific, hematopoetic-specific or tumor-suppressor miRNAs were incorporated in the 39UTR of Coxsackievirus A21 (CVA21) and protection of HeLa cells transfected with sequencecomplementary miRNA mimics was analyzed (Figure 1B)
Summary
MicroRNAs (miRNAs) are a class of small, ,22 nt regulatory RNAs that modulate a diverse array of cellular activities. Through recognition of sequence complementary target elements found most often in the 39UTR of cellular mRNAs, miRNAs posttranscriptionally regulate numerous cellular processes by way of mRNA translation inhibition or, less commonly, by catalytic mRNA degradation. It is thought that upwards of one-third of all human mRNAs are regulated by the over 700 human miRNAs that are currently known [1,2]. Many miRNAs can have tissuespecific localizations and, in addition, some are known to have cancer-specific signatures. The cellular machinery used to translate mRNAs is thought to profoundly affect miRNA regulation. While capped mRNAs are known to be amenable to both catalytic miRNA-induced cleavage and miRNA-mediated translational repression, it has been suggested that uncapped mRNAs that rely on an IRES (Internal Ribosome Entry Site) for translation initiation are not susceptible to translational repression [8][9]
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