During infection, pathogenic bacteria manipulate the host cell in various ways to permit 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 ubiquitylation 1,2 , can be induced by pathogens. However, the effects of pathogenic bacteria on SUMOylation, an essential post-translational modification in eukaryotic cells 3 remain largely unknown. Here we show that Listeria monocytogenes infection 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. The effect of LLO on Ubc9 is dependent on the poreforming 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 to infection by preventing SUMOylation of key regulatory proteins.Listeria monocytogenes is a facultative intracellular pathogen responsible for human listeriosis, a severe food-borne disease, and has emerged as a model for the study of hostpathogen interactions. This bacterium is able to cross the intestinal, maternofetal and blood

Despite numerous studies on specific sumoylated transcriptional regulators, the global role of SUMO on chromatin in relation to transcription regulation remains largely unknown. Here, we determined the genome-wide localization of SUMO1 and SUMO2/3, as well as of UBC9 (encoded by UBE2I ) and PIASY (encoded by PIAS4), two markers for active sumoylation, along with Pol II and histone marks in proliferating versus senescent human fibroblasts together with gene expression profiling. We found that, whereas SUMO alone is widely distributed over the genome with strong association at active promoters, active sumoylation occurs most prominently at promoters of histone and protein biogenesis genes, as well as Pol I rRNAs and Pol III tRNAs. Remarkably, these four classes of genes are up-regulated by inhibition of sumoylation, indicating that SUMO normally acts to restrain their expression. In line with this finding, sumoylationdeficient cells show an increase in both cell size and global protein levels. Strikingly, we found that in senescent cells, the SUMO machinery is selectively retained at histone and tRNA gene clusters, whereas it is massively released from all other unique chromatin regions. These data, which reveal the highly dynamic nature of the SUMO landscape, suggest that maintenance of a repressive environment at histone and tRNA loci is a hallmark of the senescent state. The approach taken in our study thus permitted the identification of a common biological output and uncovered hitherto unknown functions for active sumoylation at chromatin as a key mechanism that, in dynamically marking chromatin by a simple modifier, orchestrates concerted transcriptional regulation of a network of genes essential for cell growth and proliferation.[Supplemental material is available for this article.]The post-translational modification by SUMO is an essential regulatory mechanism of protein function involved in most challenges faced by eukaryotic cells (Hay 2005;Geiss-Friedlander and Melchior 2007;Hochstrasser 2009). Higher eukaryotes have three SUMO paralogs, SUMO1, SUMO2, and SUMO3, with SUMO2 and SUMO3 collectively termed SUMO2/3 because of structural and functional differences from SUMO1. Similarly to ubiquitin, SUMO is covalently conjugated to its targets via a three-step process, including unique E1 (SAE1/UBA2), E2 (UBC9 encoded by UBE2I ), and a series of E3 enzymes including the five PIAS members, CBX4, and RANBP2. The SUMO proteases (SENPs) then remove SUMO from its substrates (Yeh 2009).Investigation of numerous sumoylated transcription factors and chromatin-associated proteins reveals that, in most cases, sumoylation is associated with transcriptional repression (Ouyang and Gill 2009). Moreover, important roles for sumoylation were underscored in heterochromatin configuration (Shin et al. 2005;Maison et al. 2011), and sumoylation of core histones was shown to negatively regulate transcription in yeast and human cells (Shiio and Eisenman 2003;Nathan et al. 2006). However a growing body of evidence also links sumoyla...