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Salmonella effector SopF regulates PANoptosis of intestinal epithelial cells to aggravate systemic infection

SopF, a newly discovered effector secreted by Salmonella pathogenicity island-1 type III secretion system (T3SS1), was reported to target phosphoinositide on host cell membrane and aggravate systemic infection, while its functional relevance and underlying mechanisms have yet to be elucidated. PANoptosis (pyroptosis, apoptosis, and necroptosis) of intestinal epithelial cells (IECs) has been characterized as a pivotal host defense to limit the dissemination of foodborne pathogens, whereas the effect of SopF on IECs PANoptosis induced by Salmonella is rather limited. Here, we show that SopF can attenuate intestinal inflammation and suppress IECs expulsion to promote bacterial dissemination in mice infected with Salmonella enterica serovar Typhimurium (S. Typhimurium). We revealed that SopF could activate phosphoinositide-dependent protein kinase-1 (PDK1) to phosphorylate p90 ribosomal S6 kinase (RSK) which down-regulated Caspase-8 activation. Caspase-8 inactivated by SopF resulted in inhibition of pyroptosis and apoptosis, but promotion of necroptosis. The administration of both AR-12 (PDK1 inhibitor) and BI-D1870 (RSK inhibitor) potentially overcame Caspase-8 blockade and subverted PANoptosis challenged by SopF. Collectively, these findings demonstrate that this virulence strategy elicited by SopF aggregates systemic infection via modulating IEC PANoptosis through PDK1-RSK signaling, which throws light on novel functions of bacterial effectors, as well as a mechanism employed by pathogens to counteract host immune defense.

 

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The passage describes a study on the newly discovered effector, SopF, secreted by Salmonella pathogenicity island-1 type III secretion system (T3SS1). The study aims to elucidate the functional relevance and underlying mechanisms of SopF in modulating intestinal epithelial cells (IECs) PANoptosis induced by Salmonella enterica serovar Typhimurium (S. Typhimurium). The study reveals that SopF can attenuate intestinal inflammation and suppress IECs expulsion to promote bacterial dissemination in mice infected with S. Typhimurium. The mechanism employed by SopF involves activating phosphoinositide-dependent protein kinase-1 (PDK1) to phosphorylate p90 ribosomal S6 kinase (RSK), which down-regulates Caspase-8 activation. Caspase-8 inactivation by SopF results in the inhibition of pyroptosis and apoptosis but promotion of necroptosis. The study suggests that inhibiting PDK1 and RSK with AR-12 and BI-D1870, respectively, can potentially overcome Caspase-8 blockade and subvert PANoptosis challenged by SopF. These findings shed light on the novel functions of bacterial effectors and a mechanism employed by pathogens to counteract host immune defense.

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S2843 BI-D1870 BI-D1870 is an ATP-competitive inhibitor of S6 ribosome for RSK1/2/3/4 with IC50 of 31 nM/24 nM/18 nM/15 nM in cell-free assays, respectively; 10- to 100-fold selectivity for RSK than MST2, GSK-3β, MARK3, CK1 and Aurora B. BI-D1870 exhibits anticancer attributes including the generation of reactive oxygen species (ROS) and increases in endoplasmic reticulum (ER) stress and autophagy.

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