Viral histone-like protein co-opts host proteins to hijack cell cycle regulation

From the Avgousti Lab, Human Biology Division

Nearly two years into the pandemic, we find ourselves thinking about viruses daily. Amid the dread of hearing about yet another new SARS-CoV-2 variant and longing for normalcy, perhaps you’ve occasionally thought of how fantastic the biology behind viruses is and wondered, “what are viruses actually doing inside our cells?”. This curiosity is in part, what drives researchers in the Avgousti Lab, part of the Human Biology Division at Fred Hutch. In their recent publication in Current Biology, Dr. Daphne Avgousti and her team identified how viral proteins can co-opt host proteins to get them to do their dirty work, which in this case is to block cell cycle progression and ultimately promote infection.

Viral takeover of cellular processes is critical for their success. An important part of their takeover is controlling host chromatin to redirect resources towards viral replication. Chromatin consists of DNA wrapped around histone proteins that can be modified to cause DNA to become more or less accessible, and thus influence gene expression. Viruses can alter these histone modifications and even displace linker histones which play important roles in regulating DNA accessibility. In their recent paper, the Avgousti Lab looked at a viral histone-like protein, protein VII, which is expressed by adenoviruses, common viruses that cause cold-like symptoms in humans. They found that when protein VII is expressed in human lung epithelial cells, that the host proteins SET, a histone chaperone, and HMGB1, known to displace linker histones, became enriched in the chromatin, while linker histone H1 was depleted. They hypothesized that protein VII co-opts SET and HMGB1 to displace histone H1 from chromatin. The researchers first tested their model with genetic studies in budding yeast, Saccharomyces cerevisiae, whereupon expression of protein VII, they found that cell growth was significantly impaired. The authors reasoned that if protein VII promotes SET and HMGB1 to displace histone H1, then deletion of these host proteins might rescue this growth defect. In line with their prediction, deletion of the yeast HMGB1 and SET homologs restored normal growth in cells expressing protein VII. But could the human SET and HMGB1 proteins stand in for their deleted yeast homologs? The researchers found that indeed they could! Here, the authors discovered that if they expressed protein VII along with the human SET or HMGB1 proteins in cells lacking the corresponding yeast homolog, they were again able to cause deficient growth. This finding supports the notion that protein VII works with SET and HMGB1, or their homologs, to displace linker histones in a mechanism conserved from yeast to humans.


Viral histone-like protein, protein VII, exploits antagonism between linker histones and HMGB proteins to obstruct the cell cycle during infection. Image provided by Dr. Daphne Avgousti.

Next, the authors wanted to understand if the growth defect caused by protein VII expression was due to a block in the cell cycle. They found that cell cycle progression was halted specifically at the G2/M transition and that this was also true in human cells. Continuing their study in mammalian cells, the Avgousti Lab asked what role protein VII plays during viral infection. During adenovirus infection of human cells, early viral gene products initially work to promote proliferation. The authors were intrigued to know whether protein VII, which is expressed late in viral infection, could override the pro-proliferative effect induced by the early viral genes. The Avgousti Lab found that protein VII was able to override this pro-proliferative effect, as cells infected with protein VII expressing adenovirus (ie. wild type virus) grew significantly slower than infected cells lacking protein VII. Expression of cell cycle genes normally upregulated during G2 or mitosis negatively correlated with protein VII expression, supporting that protein VII prevents proper expression of these markers to disrupt cell cycle progression. Additionally, HMGB1 changed from diffuse nuclear staining to chromatin-bound in a protein VII-dependent fashion. Collectively, these results indicate that protein VII, together with chromatin-bound HMGB1 and SET, coordinate cell cycle disruption during infection, likely to redirect cellular resources from cell growth, towards viral reproduction.

Through examining the basic mechanisms the virus uses to take over the cell, the Avgousti Lab has identified “a highly conserved vulnerability in chromatin that is exploited by adenovirus, and could be used by other viruses to block basic cellular processes”. Moving forward, the Avgousti group is looking at the evolution of protein VII, how the interactions between protein VII and host proteins block the cell cycle, and investigating other observed phenomena such as changes in the shape of the nucleus during infection. In addition to the important discoveries made in this study, the diverse methods employed here made this an exciting project to work on. Dr. Avgousti exclaims that they used “everything from confocal microscopy to yeast genetics to test our hypothesis and these are really some of the most fun ways to do science!”.

UW/Fred Hutch Cancer Consortium member Daphne Avgousti contributed to this work.

This work was funded by the National Institute of General Medical Sciences, the National Science Foundation and Fred Hutch.

Lynch KL, Dillon MR, Bat-Erdene M, Lewis HC, Kaai RJ, Arnold EA, Avgousti DC. A viral histone-like protein exploits antagonism between linker histones and HMGB proteins to obstruct the cell cycle. Curr Biol. 2021 Dec 6;31(23):5227-5237.e7. doi: 10.1016/j.cub.2021.09.050. Epub 2021 Oct 18. PMID: 34666003.