Listeria monocytogenes impairs SUMOylation for efficient infection

Abstract

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

The arsenal of virulence factors deployed byListeria monocytogenesto promote its cell infection cycle

“…Listeria thus dampens the host response by reducing the SUMOylation level of proteins required for infection. 130,217 Proliferation of CD4 + T cells upon T cell receptor (TCR) activation is highly decreased in the presence of LLO or wild-type L. monocytogenes but not of an LLO mutant. Expression data indicate that T cell unresponsiveness induced by LLO is caused by the induction of a calcium-nuclear factor of activated T cells-dependent transcriptional program supporting the transcription of negative regulators of TCR signaling.…”

“…It is also a potent aggregator of lipid rafts 129 and recently, LLO was shown to suppress the host immune response by decreasing protein SUMOylation (see evasion of host defense section). 130 Phagosomal membrane disruption is enhanced by the bacterial phosphatidylinositol-specific and broad-range phospholipases C, PI-PLC (plcA) and PC-PLC (plcB), respectively. [131][132][133][134][135] The two enzymes cooperate with LLO in the lysis of primary and secondary vacuoles.…”

The ubiquitin system: a critical regulator of innate immunity and pathogen–host interactions

“…monocytogenes also hijacks the host ubiquitin system by secreting a pore-forming toxin, listeriolysin O, which degrades the host SUMO E2 enzyme Ubc9, thereby decreasing SUMOylation and impairing downstream TGFβ signaling. 152 …”

Listeriaen lutte avec SUMO

“…Cependant, l'effet de ces pathogènes sur certaines modifications post-traductionnelles fondamentales comme la SUMOylation reste très mal connu. Au mois d'avril, Nature a publié un article dans lequel nous démontrons que L. monocytogenes est capable d'interférer avec la SUMOylation de la cellule hôte et que cette interférence joue un rôle important dans l'infection bactérienne [9].…”