Adenovirus’s epigenetic power to reprogram cells goes beyond its ability to cause tumorous replication — G.J. Fonseca and colleagues at the Western University of Ontario report in the new Cell Host & Microbe that it’s also able to sabotage the interferon response, which usually functions as a first line of defense in infected cells.
In an April post, I interviewed Roberto Ferrari about adenovirus research and its ability to push cells back into active tumor-like replication, so I thought this bit of news was an interesting incremental step in overall knowledge of how invaders — particularly adenovirus — use epigenetics against us. What a bunch of jerks!
In particular, Fonseca and colleagues used a yeast two-hybrid screen to find out that adenovirus’s E1A protein interacts with hBre1/RNF20. That hBre1/RNF20 complex usually helps to modify histones with ubiquitin at lysine 120, which makes the DNA in the region more active. Along with other modifications that often follow in its heels, histone ubiquination can cause nearby genes to exert their effects as they send out copy after copy of full-length RNA transcripts.
Under normal circumstances, infected cells send out interferon-beta-1, which causes neighbor cells to crank up their own self-protective programs. But when adenovirus’s has already reached a neighbor cell, its E1A protein appears to completely prevent that interferon-related self protection from happening. E1A appears to bind hBre1 and prevent it from ubiquinating histones, so a whole cascade of anti-viral events never occurs.
But wait! There’s more! The protein that kicks off that interferon-related gene program by ubiquinating histones — hBre1 — seems to control expression for a virtual celebrity list of gene programs, including HOX, Notch, estrogen receptor, and even p53.
Some of these gene pathways might be incidental to adenovirus. But, at least at a superficial glance, it looks like suppressing p53 might benefit the invader’s replication, since the host cell would more easily launch into replication. There might be others too.
[Picture of a magician doing card tricks flambé by Flickr user garethjmsaunders, and it's used here under a Creative Commons license.]
Fonseca GJ, Thillainadesan G, Yousef AF, Ablack JN, Mossman KL, Torchia J, & Mymryk JS (2012). Adenovirus evasion of interferon-mediated innate immunity by direct antagonism of a cellular histone posttranslational modification. Cell host & microbe, 11 (6), 597-606 PMID: 22704620