Listeria monocytogenes impairs SUMOylation for efficient infection. Nature

Institut Pasteur, Unité des Interactions Bactéries-Cellules, Département de Biologie Cellulaire et Infection, F-75015 Paris, France.
Nature (Impact Factor: 41.46). 04/2010; 464(7292):1192-5. DOI: 10.1038/nature08963
Source: PubMed


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 ubiquitylation, can be induced by pathogens. However, the effects of pathogenic bacteria on SUMOylation, an essential post-translational modification in eukaryotic cells, 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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Available from: Hélène Neyret-Kahn, Sep 29, 2014
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    • "underscore the relevance of this response pathway in physiological or pathological conditions. Remarkably, two key PMLregulated pathways, senescence and defense against microbes, are also activated by hyper-sumoylation (Yates et al., 2008; Ribet et al., 2010; Everett et al., 2013), fully in line with our model. Future studies should thus assess the contribution of deregulated sumoylation to other PML-dependent phenotypes. "
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    ABSTRACT: The promyelocytic leukemia (PML) protein organizes PML nuclear bodies (NBs), which are stress-responsive domains where many partner proteins accumulate. Here, we clarify the basis for NB formation and identify stress-induced partner sumoylation as the primary NB function. NB nucleation does not rely primarily on intermolecular interactions between the PML SUMO-interacting motif (SIM) and SUMO, but instead results from oxidation-mediated PML multimerization. Oxidized PML spherical meshes recruit UBC9, which enhances PML sumoylation, allow partner recruitment through SIM interactions, and ultimately enhance partner sumoylation. Intermolecular SUMO-SIM interactions then enforce partner sequestration within the NB inner core. Accordingly, oxidative stress enhances NB formation and global sumoylation in vivo. Some NB-associated sumoylated partners also become polyubiquitinated by RNF4, precipitating their proteasomal degradation. As several partners are protein-modifying enzymes, NBs could act as sensors that facilitate and confer oxidative stress sensitivity not only to sumoylation but also to other post-translational modifications, thereby explaining alterations of stress response upon PML or NB loss.
    The Journal of Cell Biology 03/2014; 204(6):931-45. DOI:10.1083/jcb.201305148 · 9.83 Impact Factor
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    • "This indicates that Ubc9 is relative abundant and not limiting in the cell. However, different pathogens have evolved mechanisms to reduce Ubc9 levels to achieve global reduction in SUMO levels, as it is demonstrated for the bacterium Listeria monocytogenes and the viral protein HPVE6 (Heaton et al. 2011; Ribet et al. 2010). It would be interesting to examine the minimal levels of Ubc9 tolerated by the cell, both under constitutive and stress conditions, as well as at which levels it becomes pathogenic. "
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    ABSTRACT: Posttranslational modification of proteins by the small ubiquitin-like modifier (SUMO) is a potent regulator of various cellular events. Hundreds of substrates have been identified, many of them involved in vital processes like transcriptional regulation, signal transduction, protein degradation, cell cycle regulation, DNA repair, chromatin organization, and nuclear transport. In recent years, protein sumoylation increasingly attracted attention, as it could be linked to heart failure, cancer, and neurodegeneration. However, underlying mechanisms involving how modification by SUMO contributes to disease development are still scarce thus necessitating further research. This review aims to critically discuss currently available concepts of the SUMO pathway, thereby highlighting regulation in the healthy versus diseased organism, focusing on neurologic aspects. Better understanding of differential regulation in health and disease may finally allow to uncover pathogenic mechanisms and contribute to the development of disease-specific therapies.
    Neuromolecular medicine 08/2013; 15(4). DOI:10.1007/s12017-013-8258-6 · 3.68 Impact Factor
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    • "Specific protease activation was also observed for S. aureus a-hemolysin, which has not only been found to bind to the metalloprotease ADAM10 but also to activate it, leading to the cleavage of the adherens junction protein E-cadherin and thus disruption the epithelial barrier, in particular in the lung and skin (Inoshima et al., 2011; Inoshima et al., 2012). Finally, LLO was found to triggers aspartyl-protease-dependent degradation of Ubc9, a protein involved in SUMOylation (Ribet et al., 2010). "
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