[News from this site] On February 19, the team of Professor Gao Xiang from the State Key Laboratory of Microbial Technology of Shandong University and Professor Jorge Galán from Yale University School of Medicine teamed up in the”Nature Microbiology” (Nature Microbiology, five years IF= 16.29) published a research paper entitled”The Salmonella Effector Protein SopD targets Rab8 to positively and negatively modulate the inflammatory response”. Professor Gao Xiang and Professor Jorge Galán are the co-corresponding authors of the study. Lian Huan, a postdoctoral fellow in the Jorge Galán group, Jiang Kun, a postdoctoral fellow in the Gao Xiang group, and Tong Ming, a doctoral student, are the co-first authors. The State Key Laboratory of Microbial Technology of Shandong University is the first author unit and the corresponding author unit.
Salmonella, as a common food-borne pathogen, often infects the host through contaminated food or water sources. After human infection, it usually manifests as typhoid fever or gastroenteritis. In order to survive, multiply and spread in the host, Salmonella secretes effector proteins into the host cell through its type III secretion system. The SopD family is a very conserved effector protein unique to Salmonella. Studies have shown that this family plays an important role in the invasion, colonization and later systemic infection of Salmonella, but the specific molecular mechanism is unknown. In order to solve this problem, the study explained the function and mechanism of SopD through a combination of microbial genetics, biochemistry, structural biology, and cell biology.
First of all, this study screened the potential targets of SopD based on the GTPase activity detection experiment. The results showed that SopD is a GAP (GTPase activating protein) that specifically acts on Rab8 small G protein. By analyzing the complex crystal structure of SopD and its target Rab8 protein in host cells, it is found that the interaction interface between the two is quite different from the classical GAP-Rab, and this interaction interface is the same as the GDI-Rab interaction interface. There is a conflict in space, so it is speculated that SopD has another function similar to GDF (GDI replacement factor) in addition to GAP activity. This hypothesis is achieved through both in vitro competitive CO-IP experiments and in vivo cell infection experiments. It was verified.
This study revealed the mechanism of action of the Salmonella effector protein SopD at the molecular level for the first time, and unexpectedly found that SopD is a rare effect protein that also has both “yin-yang” functions. On the one hand, SopD inhibits the anti-inflammatory pathway mediated by Rab8 through its GAP activity, enhances the inflammatory response, and promotes the invasion and proliferation of Salmonella. On the other hand, SopD can also release Rab8 from its tight binding with GDI through its GDF-like function, and promote the reactivation of Rab8 protein; by enhancing the anti-inflammatory response mediated by Rab8, it helps host cells to restore homeostasis, which is beneficial to Salmonella Long-term colonization in host cells. The above research results not only enriched the understanding of the pathogenic mechanism of Salmonella, but also demonstrated an outstanding product of the Salmonella effector protein in the evolution process, laying a theoretical foundation for the subsequent research on SopD protein and the development of antibacterial drugs targeting SopD .
The research work was funded by the National Key Research and Development Program, the National Natural Science Foundation of China, the Shandong Natural Science Foundation Major Basic Program, the Taishan Young Scholars Program, and the Shandong University Youth Interdisciplinary Science Innovation Group. . The public technology platform for life environment research of Shandong University and the Shanghai synchrotron radiation source provided important support for this work. Professor Gao Xiang’s team mainly used enteric Bacteroides and Salmonella as model bacteria to study the molecular mechanism of the interaction between intestinal bacteria, enteric pathogens and host.
Professor Gao Xiang’s research group website:https://gaolab.qd.sdu.edu.cn/