During infection, pathogenic bacteria manipulate the host cell in various ways to allow their own replication, propagation and escape from host immune responses. Post-translational modifications are unique mechanisms that allow cells to rapidly, locally and specifically modify activity or interactions of key proteins. Some of these modifications, including phosphorylation and ubiquitylation1,2, can be induced by pathogens. However, the effects of pathogenic bacteria on SUMOylation, an essential post-translational modification in eukaryotic cells3, remain largely unknown. Here we show that infection with Listeria monocytogenes leads to a decrease in the levels of cellular SUMO-conjugated proteins. This event is triggered by the bacterial virulence factor listeriolysin O (LLO), which induces a proteasome-independent degradation of Ubc9, an essential enzyme of the SUMOylation machinery, and a proteasome-dependent degradation of some SUMOylated proteins. The effect of LLO on Ubc9 is dependent on the pore-forming capacity of the toxin and is shared by other bacterial pore-forming toxins like perfringolysin O (PFO) and pneumolysin (PLY). Ubc9 degradation was also observed in vivo in infected mice. Furthermore, we show that SUMO overexpression impairs bacterial infection. Together, our results reveal that Listeria, and probably other pathogens, dampen the host response by decreasing the SUMOylation level of proteins critical for infection.
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We thank V. Villiers for technical assistance. Work in the P.C. laboratory received financial support from Institut Pasteur, INSERM, INRA and European Research Council (ERC, Advanced Grant 233348). We further acknowledge support by research grants from the Fund for Scientific Research – Flanders (Belgium) (project number G.0042.07), the Concerted Research Actions (project BOF07/GOA/012) from Ghent University and the Inter University Attraction Poles (IUAP06). D.R. is supported by a fellowship from the Association pour la Recherche sur le Cancer, F.I. is a Research Assistant of the Research Foundation – Flanders (Fonds Wetenschappelijk Onderzoek – Vlaanderen) and P.C. is an international research scholar of the Howard Hughes Medical Institute.
Author Contributions P.C. planned the project. D.R., K.G., J.V., A.D. and P.C. designed the research, D.R., M.H., E.G., M.-A.N., F.I. and H. N.-K. performed the experiments. D.R., M.H., K.G., J.V. and P.C. analysed the experiments. D.R. and P.C. wrote the paper and co-authors commented on it.
This file contains Supplementary Figures 1-4 with legends, Supplementary Tables 1-3 and Supplementary References.
About this article
Scientific Reports (2015)