The Salmonella effector protein SopD targets Rab8 to positively and negatively modulate the inflammatory response

Abstract

The food-borne bacterial pathogen Salmonella Typhimurium uses a type III protein secretion system to deliver multiple proteins into host cells. These secreted effectors modulate host cell functions and activate specific signalling cascades that result in the production of pro-inflammatory cytokines and intestinal inflammation. Some of the Salmonella -encoded effectors counter this inflammatory response and help to preserve host homeostasis. We demonstrate that the Salmonella effector protein SopD, which is required for pathogenesis, functions to both activate and inhibit the inflammatory response by targeting the Rab8 GTPase, a negative regulator of inflammation. We show that SopD has GTPase activating protein activity for Rab8, and therefore inhibits this GTPase and stimulates inflammation. We also show that SopD activates Rab8 by displacing it from its cognate guanosine dissociation inhibitor resulting in the stimulation of a signaling cascade that suppresses inflammation. We solved the crystal structure of SopD in association with Rab8 to 2.3 Å resolution, which reveals a unique contact interface underlying these complex interactions. These findings show the remarkable evolution of a bacterial effector protein to exert both agonistic and antagonistic activities toward the same host cellular target to modulate the inflammatory response.

Salmonella effector SopD promotes plasma membrane scission by inhibiting Rab10

“…In future studies, it will be important to determine whether inhibition of Rab8A by SopD (and/or SopD2 21 ) impacts other pathways or stages of infection. Of note, during the review of this manuscript Galan and colleagues revealed that SopD can target Rab8 to positively and negatively modulate the inflammatory response 42 .…”

MicroRNA-5112 Targets IKKγ to Dampen the Inflammatory Response and Improve Clinical Symptoms in Both Bacterial Infection and DSS-Induced Colitis

“…Salmonella infections can cause diarrhea, inflammation, gastroenteritis, and systemic infections ( 24 , 25 ). Salmonella enterica serovar enteritidis ( S .…”

“…Exogenous miR-5112 AgomiR Suppresses Salmonella-Induced Inflammation and Delays Salmonella-Induced Death in a Streptomycin Pre-Treated Mouse Model Salmonella infections can cause diarrhea, inflammation, gastroenteritis, and systemic infections (24,25). Salmonella enterica serovar enteritidis (S. enteritidis) is one of the most common serotypes of salmonellosis in humans.…”

Structural biology of the invasion arsenal of Gram‐negative bacterial pathogens

“…7G) and, indeed, the R315A mutation abolished SopD2 GAP activity [164]. Very recently, the structure of SopD with Rab8A has been elucidated [165]. Interestingly, Rab8A in this complex is in a GDP‐bound state and binds SopD on the opposite side to Arg 312.…”

“…It has been documented that SopD2 plays the role of a GAP protein for Rab34 [164]. Its paralog SopD has been shown to have a GAP function for Rab8 but also it acts as GDI displacement factor later in infection [165]. The structures of SopD2 and its paralog SopD have been solved and indicated that they adopt a novel fold [163].…”