The mi-RNA game of HCV

Howdy fellows,

            Before i begin to talk, i need to make a point. Often many people think and ask me how do i get to write so many things. The answer is am not at the top of knowledge. Instead, am at the bottom. When i come across a topic that happened to be interesting enough to me, i try to gather some knowledge about it. And the notes that i make is what is written in blog. I end up with few errors (I must admit it!!), at times and when i come to know i try to make the correction. Ok, so now that i made the clarification i can go ahead. Right??!!

           Hepatitis C Virus, henceforth in this writing referred as HCV (Hepacivirus genus) is a member of Flavivirus. They are made up of a ssRNA of + sense. And of-course they are enveloped. Historically they came into the main picture as a non A non B type of hepatitis virus. (Click here to read more about the HCV features)

Fig 1: Structure of Hepatitis C virus (Source)

Fig 2: Host and viral factors in the immunopathogenesis of primary hepatitis C virus infection (Andrew R Lloyd etal; Source)

          Being a + sense RNA virus, what do you expect the virus to do? Indeed, it just enters the cell, and codes for proteins, makes new genome copies and escapes of the cell. Meanwhile the cell tries to defend itself by producing some RNA interference. By the way did i tell you what's this edition of blog all about? Oh, right time to tell. The HCV just used this RNA interference pathway to its best. Puzzling isn't it! This is about a micro RNA 122 seen in abundance in the hepatic cells that aids the replication of the HCV.

Video: Replication of HCV

          The entire discussion about this needs to be put into 3 sections- MicroRNA (miRNA), miRNA 122 and how the HCV hijacks the mir122 for survival.

The concept of RNA interference:
        

      RNAi or RNA interference is a normal physiological process used for regulation of RNA in cells. The work initially began from studies in C. elegans, now is a major tool in molecular studies. A minimum of 3 components is involved in RNA interference in higher eukaryotes: Drosha, Dicer, and Argonaute (Ago) gene family members. The current working model flows so. A mi-RNA is processed by drosha and dicer to produce si-RNA. This produces a defined dsRNA containing about 17–23 bp of dsRNA and 3′ 2-nucleotide overhangs. These small RNA is incorporated into RISC (RNA induced silencing complex). The figure illustrates a model of micro RNA and its processing (Source).

       RISC is a large multimeric complex which incorporates the miRNA or the siRNA into itself. The RNA sequence helps in recognizing the complementary mRNA, mainly through base paring to the 3′-untranslated region of target messenger RNAs (mRNAs). On successful recognition, RNAase comes to play and the targeted RNA is cleaved.

Fig 3: RNAi pathway (Source)

Fig 4: Mechanism of microRNA (miRNA)-mediated gene regulation (Source)

What we know about mi-RNA 122:

          miRNA 122 is a highly conserved vertebrate specific RNA species, with high activity in liver. It is being studied in immense detail, owing to its role in the lipid pathways. It is estimated that the miRNA 122 makes up nearly 70% of the hepatic cell miRNA content. The consequence of miR-122 inhibition in normal is lowering of plasma cholesterol (Click here for source). From this its clear that the miRNA 122 is in abundance in the hepatic cell and thus makes sense for HCV which resides in the hepatocytes to use it.

Fig 5: Structure of miRNA 122 and expression profile (Source)

miRNA 122 and HCV:

Fig 6: Action of miRNA 122 in stabilising HCV mRNA (Source)

    The first important idea that, the micro RNA 122 is involved in upholding the cause of HCV was suggested by Jopling CL etal (Link here and here). The paper in PNAS by Shimakami T etal, have shown that the miR-122 instead of binding to the HCV 3' UTR sequence as it must be doing, it binds to the 5' UTR and stabilizes the set HCV genome, protecting it against the 5' exonulcease. In a sense, this caps the 5' region (Link). A fantastic discussion on the whole issue is well discussed in TWiV (Episode 180) podcast and i really cannot make a better statement than they already have.

In short, my take home message is that miR122 is a potential target of treatment against HCV. The interaction involves stabilization of HCV  at 5' end.

Shimakami T, Yamane D, Jangra RK, Kempf BJ, Spaniel C, Barton DJ, & Lemon SM (2012). Stabilization of hepatitis C virus RNA by an Ago2-miR-122 complex. Proceedings of the National Academy of Sciences of the United States of America, 109 (3), 941-6 PMID: 22215596


Further reading:

1. Jopling C. RNA Biol. 2012 Feb 1;9(2):137-42. Epub 2012 Feb 1. Liver-specific microRNA-122: Biogenesis and function. (Link).