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

Abstract

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.

Toll‐like receptor signalling cross‐activates the autophagic pathway to restrictSalmonellaTyphimurium growth in macrophages

“…Typhimurium‐infected macrophages in a T3SS‐independent manner. Brink et al () recently reported that Ssel, an SPI‐2 effector, induces AKT phosphorylation by activating the G protein in macrophages. Here, we tested whether S .…”

“…Intriguingly, phosphorylation of another mTOR substrate, S6K1, and its downstream molecule, S6, is not decreased but rather increased, whereas the status of ULK1 S757 phosphorylation is not reported (Tattoli, Sorbara, Vuckovic, et al, ). Brink et al () found that S . Typhimurium infection of bone marrow‐derived macrophages leads to increased AKT and S6K1 phosphorylation.…”

“…Bar length: 20 μm. * P < .05 and ** P < .01, compared with uninfected control; # P < .05 and ## P < .01, compared with S. T infection Brink et al (2018) recently reported that Ssel, an SPI-2 effector, induces AKT phosphorylation by activating the G protein in macrophages. Here, we tested whether S. Typhimurium infection induced phosphorylation of AKT and two downstream molecules, S6K1 T389 and ULK S757 .…”

Salmonella Virulence and Immune Escape

“…Therefore, it seems that manipulating the antigen presentation capability of antigen presenting cells is another important strategy of pathogens for suppressing and escaping the host immune responses [224]. SseI has been shown to block the migration of DCs to lymphocytes [225]. Moreover, the major histocompatibility complex (MHC) plays an important role in combating the Salmonella during the later stages of infection [226,227].…”

A cysteine protease–like domain enhances the cytotoxic effects of the Photorhabdus asymbiotica toxin PaTox

“…This modification impairs Rho signaling and results in actin cytoskeleton disintegration, blockade of phagocytosis, and death of insect larvae. The second effector domain is a deamidase (PaTox D ) that resembles the type III secreted effector SseI from Salmonella typhimurium (11). It deamidates a catalytic glutamine residue of heterotrimeric G␣ proteins, resulting in the permanent activation of the GTPase signaling molecule (10).…”