What is ICP27 trying to tell us? One of you could get a PhD if you figure it out !

It wouldn’t be the first time a viral protein led us to an important cellular mechanism. Consider what the polio virus taught us about the translation of mRNA into protein. It cleaves two components of eIF-4F (eukaryotic Initiation (of ribosome translation of mRNA into protein) Factor 4F totally shutting down synthesis of mRNAs with a cap on their 5′ end (which is most of them). Poliovirus proteins don’t have these caps so their proteins continue to be made.

Well this brings us to ICP27 (Infected Cell Protein 27) a product of the Herpes Simplex virus. You can read all about it in [ Proc. Natl. Acad. Sci. vol. 113 pp. 12256 – 12261 ’16 ]. ICP27 is essential for herpes virus infection. This work shows that it inhibits intron splicing (but in under 1% of cellular genes) and also promotes the use of alternative 5′ splice sites.

It also induces the expression of pre-mRNAS prematurely cleaved and polyAdenylated from cryptic polyAdenylation signals located in intron 1 or intron 2 of an amazing 1% of all cellular genes. These prematurely cleaved and polyAdenylated mRNA sometimes contain novel open reading frames (ORFs). They are typically intronless (they should be) and under 2 kiloBases long. They are expressed early during viral infection and efficiently exported to cytoplasm. The ICP27 targeted genes are GC rich (as are all Herpes simplex genes), contain cytosine rich sequences near the 5′ splice site.

The paper also showed that optimization of splice site sequences, or mutation of nearby cytosines eliminated ICP27 mediated splicing inhibition. Introduction of cytosine rich sequences to an ICP27 INsensitive splicing reporter conferred susceptibility to ICP27.

How is this going to help you get a PhD? Ask yourself. What are cryptic polyAdenylation signals doing in the first two introns in so many genes? It seems obvious (to me) that as well as the virus the cell is using them for some purpose. It isn’t hard to mutate something to the signal for polyadenylation AAUAAA. Interestingly cleavage doesn’t occur here, but 30 nucleotides or so downstream. The sequence occurs every 4^6 == 4096 nucleotides (if they’re random). I’m not sure what the total length of introns #1 and #2 are of our 20,000 or so protein coding genes, but someone should be able to find out and see if 200 occurrences of this sequence is more than would be expected by chance.

The plot thickens when the paper notes that “Over 200 genes are affected by ICP27. Over 30 (including PML, STING, TRAF6, PPP6C, MAP3K7, FBXw11, IFNAR2, NKFB1, RELA and CREBP are related to the immune pathway). Do you think the cell doesn’t use this pathway as well?

What about the existence of other viral (and cellular) proteins doing the same sort of thing (but on different introns perhaps). What are those novel open reading frames in the alternatively spliced mRNAs doing?

Fascinating stuff. Time to get busy if you’re an enterprising grad student, or young faculty member.

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  • Bryan  On November 1, 2016 at 11:20 am

    Depletion of splicing sites and enrichment of polyadenylation sites seems to be the mechanism by which eukaryotic cells deal with the fact that opening chromatin at the promoter seems to promote transcription in both directions (see https://www.ncbi.nlm.nih.gov/pubmed/23792564). In general, depletion of the U1-snRNPs that mediate splicing leads to truncation of many transcripts at cryptic splice sites, very much in agreement with the results of the PNAS paper.

  • Melchizidek  On November 4, 2016 at 3:45 pm

    Whither the connection between altitude and MS?

    Higher latitude is significantly associated with an earlier age of disease onset I multiple sclerosis, Journal of Neurology Neurosurgery & Psychiatry, DOI: 10.1136/jnp-2016-314013

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