The Brucella effector protein BspF crotonylates TRIM38 to inhibit NF-κB and MAPK signaling pathway.

Abstract Brucellosis is caused by Brucella, which is a highly prevalent intracellular parasite. Type IV secretion system(T4SS) is an important virulence factor of Brucella. T4SS secretes 16 effector proteins, which affect the intracellular transport of Brucella-containing vacuole and regulate the host immune response, helping Brucella to survive and replicate in host cells. In our previous crotonylation proteomics data of HEK-293T cell proteintriggered by BspF, we found BspF crotonylated on TRIM38, which is an important modulator in the pathways of inflammation, and the crotonylation site is K142. Therefore, it is speculated that BspF may be involved in the regulation of host inflammatory response during Brucella infection. In this study, we found BspF-mediated TRIM38K142 crotonylation promotes the ubiquitination of Tumor necrosis factor receptor (TNFR)-associated factor 6 (TRAF6), leading to the degradation of TRAF6, thereby inhibiting the transduction of NF-κB, p38 MAPK and JNK MAPK signaling pathways and inhibits the secretion of pro-inflammatory factors IL-1β, IL-6 and IL-8, which finally helps Brucella to promote intracellular survival. This study provides a new theoretical basis for Brucella to achieve intracellular survival by regulating host innate immunity through T4SS, and provides an important reference for the study of non-histone crotonylation.