ISG15 is an interferon-stimulated, linear di-ubiquitin-like protein, with anti-viral activity. The role of ISG15 during bacterial infection remains elusive. We show that ISG15 expression in nonphagocytic cells is dramatically induced upon Listeria infection. Surprisingly this induction can be type I interferon independent and depends on the cytosolic surveillance pathway, which senses bacterial DNA and signals through STING, TBK1, IRF3 and IRF7. Most importantly, we observed that ISG15 expression restricts Listeria infection in vitro and in vivo. We made use of stable isotope labeling in tissue culture (SILAC) to identify ISGylated proteins that could be responsible for the protective effect. Strikingly, infection or overexpression of ISG15 leads to ISGylation of ER and Golgi proteins, which correlates with increased secretion of cytokines known to counteract infection. Together, our data reveal a previously uncharacterized ISG15-dependent restriction of Listeria infection, reinforcing the view that ISG15 is a key component of the innate immune response.Listeria monocytogenes is a bacterium that can cause serious food poisoning in humans. Infections with this bacterium can be particularly dangerous to young children, pregnant women, the elderly, and individuals with weakened immune systems because they are more susceptible to developing serious complications that can sometimes lead to death.The bacteria infect cells in the lining of the human gut. Cells that detect the bacteria respond by producing proteins called interferons and other signaling proteins that activate the body's immune system to fight the infection. One of the genes that the interferons activate encodes a protein called ISG15, which helps to defend the body against viruses. However, it is not clear what role ISG15 plays in fighting bacterial infections.Here, Radoshevich et al. studied the role of ISG15 in human cells exposed to L. monocytogenes. The experiments show that ISG15 levels increase in the cells, but that the initial increase does not depend on Interferon proteins. Instead, ISG15 production is triggered by an alternative pathway called the cytosolic surveillance pathway, which is activated by the presence of bacterial DNA inside the cell.Further experiments found that ISG15 can counteract the infections of L. monocytogenes both in cells grown in cultures and in living mice. ISG15 modifies other proteins in the cell to promote the release of proteins called cytokines that help the body to eliminate the bacteria. Radoshevich et al.'s findings reveal a new role for ISG15 in fighting bacterial infections. A future challenge will be to understand the molecular details of how ISG15 triggers the release of cytokines.
Radoshevich, L., Impens, F., Ribet, D., Quereda, J. J., Tham, T. N., Nahori, M. A., … Cossart, P. (2015). ISG15 counteracts Listeria monocytogenes infection. ELife, 4(AUGUST2015). https://doi.org/10.7554/eLife.06848