Loison, L.; Hure, M.; Lefranc, B.; Leprince, J.; Coeffier, M.; Ribet, D.

Gut bacteria play key roles in intestinal physiology, via the secretion of diversified bacterial effectors. Many of these effectors remodel the host proteome, either by altering transcription or by regulating protein post-translational modifications. SUMOylation, a ubiquitin-like post-translational modification playing key roles in intestinal physiology, is a target of gut bacteria. Mutualistic gut bacteria can promote SUMOylation, via the production of short- or branched-chain fatty acids (SCFA/BCFA). In contrast, several pathogenic bacteria were shown to dampen SUMOylation in order to promote infection. Here, we challenge this dichotomic vision by showing that Staphylococcus warneri, a non-pathogenic bacterium of the human gut microbiota, decreases SUMOylation in intestinal cells. We identified that Warnericin RK, a hemolytic toxin secreted by S. warneri, targets key components of the host SUMOylation machinery, leading to the loss of SUMO-conjugated proteins. We further demonstrate that the dampening of SUMOylation triggered by Warnericin RK promotes inflammation, and, more particularly, TNFalpha-dependent intestinal inflammatory responses. Together, these results highlight the diversity of mechanisms used by non-pathogenic bacteria from the gut microbiota to manipulate host SUMOylation. They further highlight that changes in gut microbiota composition may impact intestinal inflammation, by changing the equilibrium between bacterial effectors promoting or dampening SUMOylation.