Viruses have been part of animals and humans for eons. When viruses invade a cell, they can infiltrate the nucleus with their genome and become part of the genome of the infected organism. Viruses transfer their genes between various organisms, as well as between tissues containing well differentiated cells inside a living creature. But how they uncoat their well-packed genes and release them to cause infection is largely unknown.
The research group of Urs Greber, professor at the Institute of Molecular Life Sciences of the University of Zurich (UZH), has now for the first time identified a protein in human cells that is key for successful viral DNA uncoating: the ubiquitin-ligase Mind bomb 1 (Mib1). “The protein enables adenoviruses to uncoat their DNA and discharge it into the nucleus – which is necessary for successful infection,” says Greber. If the protein is not produced or fails to work properly, the viruses can penetrate into the cell and reach the nuclear membrane, but they remain stuck on the porous structures of the nuclear envelope. “This finding opens up a new possibility for developing anti-viral therapies that block Mib1 in well differentiated cells,” says Greber. At present, there are no effective drugs to combat these widespread viruses.
Researchers found the protein by switching off most of the genes in human cells of the lung epithelium using RNA interference one by one, and then testing whether adenoviruses could infect the cells. “When we inhibited the gene for Mib1 or knocked it out using CRISPR-Cas technology, the virus infection rate declined drastically. Practically all adenoviruses remained stuck at the pore structures outside of the nucleus,” says Greber. As soon as these cells, after genetic interventions, produced small amounts of Mib1 again, the Mib1 reached the viruses at the nuclear pores, and the viruses uncoated their genes and infected the cells.
Michael Bauer, Justin W. Flatt, Daria Seiler, Bettina Cardel, Mario Emmenlauer, Karin Boucke, Maarit Suomalainen, Silvio Hemmi, and Urs F. Greber. The E3 Ubiquitin Ligase Mind Bomb 1 Controls Adenovirus Genome Release at the Nuclear Pore Complex. Cell Reports. 17 December 2019. DOI: 10.1016/j.celrep.2019.11.064