Imitation is the sincerest form of flattery, they say. But instead of flattery, the influenza virus (and maybe many other viruses) imitates histones to make people sick. That kind of flattery we could do without. Researchers in NY and the U.K. discovered that influenza A (H3N2)—one of the strains that cause seasonal flu outbreaks—hijacks the body’s defenses with a protein that mimics a histone H3 tail.
The scientists knew that a sequence in histone methyltransferase G9a resembles a histone H3 tail, and that it can compete with real histones for protein binding. So, the team thought that pathogens might use a similar trick to mess with human cells.
The team searched in silico for pathogen proteins that had a histone-tail-like unstructured domain at one end and could accumulate in the nucleus. They found that the NS1 protein from the influenza A (H3N2) virus fits the bill. Here’s what else they learned:
- The NS1 protein can be a substrate for histone-modifying enzymes in vitro, and it was methylated and acetylated in infected human cells.
- NS1 and histone H3 bind to the human PAF1 transcription elongation complex (hPAF1C), which is involved in the antiviral response.
- NS1 accumulates on induced antiviral gene promoters.
- Cells infected with the influenza A (H3N2) virus had evidence of impaired transcriptional elongation on antiviral genes, but not on housekeeping genes.
The researchers conclude, “Our findings provide unambiguous proof for the ability of the NS1 tail to interfere directly with hPAF1C-driven transcription of antiviral genes.” They say that the findings could offer a new avenue for the design of very specific anti-influenza therapies.
Read all of the non-contagious details at Nature, March 2012.