Salmonella Typhimurium effector SseI inhibits chemotaxis and increases host cell survival by deamidation of heterotrimeric Gi proteins

• Published in: PLoS pathogens 2018-08, Vol.14 (8), p.e1007248-e1007248
• Main Authors: Brink, Thorsten, Leiss, Veronika, Siegert, Peter, Jehle, Doris, Ebner, Julia K, Schwan, Carsten, Shymanets, Aliaksei, Wiese, Sebastian, Nürnberg, Bernd, Hensel, Michael, Aktories, Klaus, Orth, Joachim H C
• Format: Article
• Language: English
• Subjects: 1-Phosphatidylinositol 3-kinase; AKT protein; Amino acids; Animals; Bacterial Proteins - genetics; Bacterial Proteins - physiology; Biology; Biology and Life Sciences; Cell activation; Cell adhesion & migration; Cell migration; Cell survival; Cell Survival - genetics; Chemotaxis; Chemotaxis - genetics; Coding; Deamination - genetics; Dendritic cells; Effector cells; Effectors; Female; Foodborne diseases; Gastroenteritis; Glutamine; GTP-Binding Protein alpha Subunits, Gi-Go - chemistry; GTP-Binding Protein alpha Subunits, Gi-Go - metabolism; HEK293 Cells; HeLa Cells; Host-Pathogen Interactions - genetics; Humans; Immunocompromised hosts; Infections; Intracellular; Kinases; Male; Medicine and Health Sciences; Mice; Mice, Inbred C57BL; Mice, Knockout; Mode of action; Neutrophils; Pathogenicity; Pathogenicity islands; Pathogens; Phosphorylation; Protein Multimerization - genetics; Protein Processing, Post-Translational - genetics; Proteins; RAW 264.7 Cells; Research and Analysis Methods; Salmonella; Salmonella Infections - metabolism; Salmonella Infections - pathology; Salmonella typhimurium - genetics; Salmonella typhimurium - metabolism; Survival; TOR protein; Type III Secretion Systems - genetics; Type III Secretion Systems - metabolism; Type III Secretion Systems - physiology
• ISSN: 1553-7374; 1553-7366; 1553-7374
• DOI: 10.1371/journal.ppat.1007248

Salmonella enterica serotype Typhimurium (S. Typhimurium) is one of the most frequent causes of food-borne illness in humans and usually associated with acute self-limiting gastroenteritis. However, in immunocompromised patients, the pathogen can disseminate and lead to severe systemic diseases. S. Typhimurium are facultative intracellular bacteria. For uptake and intracellular life, Salmonella translocate numerous effector proteins into host cells using two type-III secretion systems (T3SS), which are encoded within Salmonella pathogenicity islands 1 (SPI-1) and 2 (SPI-2). While SPI-1 effectors mainly promote initial invasion, SPI-2 effectors control intracellular survival and proliferation. Here, we elucidate the mode of action of Salmonella SPI-2 effector SseI, which is involved in control of systemic dissemination of S. Typhimurium. SseI deamidates a specific glutamine residue of heterotrimeric G proteins of the Gαi family, resulting in persistent activation of the G protein. Gi activation inhibits cAMP production and stimulates PI3-kinase γ by Gαi-released Gβγ subunits, resulting in activation of survival pathways by phosphorylation of Akt and mTOR. Moreover, SseI-induced deamidation leads to non-polarized activation of Gαi and, thereby, to loss of directed migration of dendritic cells.