Thursday, 21 November 2013

The Great RNA Confusion: RNAi - miRNA - siRNA - do you know the difference?

Principles of Molecular Virology Principles of Molecular Virology, Chapter 6 (Virus Infection), discusses RNA interference and virus infection.

RNA Interference RNA interference (RNAi) is an important set of pathways that are used to regulate gene expression. RNAi is a blanket term which can refer to both small interfering RNAs (siRNAs) and microRNAs (miRNAs). There are important differences between siRNAs and miRNAs but I'll get to those later. To start, it's a good idea to watch this introductory video about RNAi:

There is some overlap in the molecular mechanisms used by siRNAs and miRNAs, so what's the difference? That is summed up in this table (based on MicroRNA gets down to business. (2007) Nature Biotechnology 25, 631-638 doi: 10.1038/nbt0607-631):


In "lower organisms" such as plants, fungi and insects, siRNA can not only regulates the expression of endogenous genes, but is a major factor in innate immunity, silencing the expression of foreign genetic material such as viruses. Both siRNA and miRNA regulate gene expression, but do so in different ways. siRNA is specific to a particular target (gene sequence) whereas miRNA is not and a single miRNA can potentially regulate the expression of many different genes. Thus it is possible to regard miRNA as the more "highly evolved" system, especially as siRNA does not occur in higher animals such as mammals, which have replaced siRNA with other antiviral mechanisms such as interferons.

Or so we thought.

Recently there has been a lot of discussion about two controversial papers published in Science which claimed to show that miRNA could exert antiviral activity in mice, at least in some circumstances (Antiviral RNA interference in mammalian cells. (2013) Science, 342(6155), 235-238; RNA interference functions as an antiviral immunity mechanism in mammals. (2013) Science, 342(6155), 231-234). These papers only found evidence for antiviral siRNA activity in stem cells and newborn mice and many scientists think siRNA is not a major part of the innate immune system in adult animals. Interestingly, there is evidence that siRNA may be turned on in responses to virus infection, but rather than acting directly against the virus, it may be used to regulate the interferon response (Reciprocal Inhibition between Intracellular Antiviral Signaling and the RNAi Machinery in Mammalian Cells. (2013) Cell host & microbe, 14(4), 435-445 and: Is RNA interference a physiologically relevant innate antiviral immune response in mammals? (2013) Cell host & microbe, 14(4), 374-378).

That still leaves the fact that in mammals miRNA is a powerful regulator of gene expression, including virus genes. Many viruses use make miRNA to control their own gene expression and that of their host cells (Virus-Encoded microRNAs: An Overview and a Look to the Future. (2012) PLoS Pathog 8(12): e1003018. doi:10.1371/journal.ppat.1003018). On infection of a host cell, viruses encounter a range of miRNA species, many of which have been shown to restrict virus gene expression. Thus they have had to evolve a range of mechanisms to evade miRNA restriction is the same way that they have evolved other mechanisms to mitigate the impact of innate immunity. These include:

The evolutionary arms race between virus and host continues...