Mammalian GTPase-activating proteins (GAPs) can inhibit innate immunity signaling in a spatiotemporal fashion; however, the role of bacterial GAPs in mediating innate immunity remains unknown. In this study, we show that BspI, a Brucella type IV secretion system (T4SS) effector protein, containing a GAP domain at the C terminus, negatively regulates proinflammatory responses and host protection to Brucella abotus infection in a mouse model. In macrophages, BspI inhibits the activation of inositol-requiring enzyme 1 (IRE1) kinase, but it does not inhibit activation of ATF6 and PERK. BspI suppresses induction of proinflammatory cytokines via inhibiting the activity of IRE1 kinase caused by VceC, a type IV secretion system effector protein that localizes to the endoplasmic reticulum. Ectopically expressed BspI interacts with IRE1 in HeLa cells. The inhibitory function of BspI depends on its GAP domain but not on interaction with small GTPase Ras-associated binding protein 1B (RAB1B). Collectively, these data support a model where BspI, in a GAP domain–dependent manner, inhibits activation of IRE1 to prevent proinflammatory cytokine responses.
Brucellosis is a zoonotic bacterial disease posing serious threats to the health of humans and animals. Currently, effective therapeutics available for brucellosis are in urgent demand. Brucellosis is transmitted to humans through diet or contact with infected animals. Several live‐attenuated vaccine strains are commercially available for animals, such as Brucella melitensis Rev.1, Brucella abortus S19, and RB51. However, no secure and effective vaccine for human beings has been developed yet against brucellosis, for which antibiotic therapy is the most frequently used and valid. Nevertheless, excessive antibiotics could prohibit the sensitivity of Brucella and develop resistance in humans. In addition, other clinical treatments, such as surgical treatment, have little effect on brucellosis. Therefore, novel treatment protocols should be explored. Based on numerous experimental studies, it is speculated that brucellosis can be fundamentally treated by inhibiting the activation of the type IV secretion system and changing the acidic environment of eBCV. In addition, previous literature showed that traditional Chinese medicine therapy also had certain efficacy, providing a new perspective angle for the exploration of treatment options.
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