GogB Is an Anti-Inflammatory Effector that Limits Tissue Damage during Salmonella Infection through Interaction with Human FBXO22 and Skp1

Abstract

Bacterial pathogens often manipulate host immune pathways to establish acute and chronic infection. Many Gram-negative bacteria do this by secreting effector proteins through a type III secretion system that alter the host response to the pathogen. In this study, we determined that the phage-encoded GogB effector protein in Salmonella targets the host SCF E3 type ubiquitin ligase through an interaction with Skp1 and the human F-box only 22 (FBXO22) protein. Domain mapping and functional knockdown studies indicated that GogB-containing bacteria inhibited IκB degradation and NFκB activation in macrophages, which required Skp1 and a eukaryotic-like F-box motif in the C-terminal domain of GogB. GogB-deficient Salmonella were unable to limit NFκB activation, which lead to increased proinflammatory responses in infected mice accompanied by extensive tissue damage and enhanced colonization in the gut during long-term chronic infections. We conclude that GogB is an anti-inflammatory effector that helps regulate inflammation-enhanced colonization by limiting tissue damage during infection.

Impact ofSalmonella entericaType III Secretion System Effectors on the Eukaryotic Host Cell

“…This interaction targets GogB to the Skp, Cullin, F-box containing (SCF) ubiquitin ligase complex to dampen the host inflammatory response by inhibiting IκBα degradation and NFκB activation. Therefore, GogB can be seen as an anti-inflammatory effector that manipulates the host ubiquitination system to prevent host inflammatory responses following colonization in order to limit tissue damage and bacterial burden during chronic infection [183].…”

FBXO22 Protein Is Required for Optimal Synthesis of the N-Methyl-d-Aspartate (NMDA) Receptor Coagonist d-Serine

“…1A). FBXO22a controls the degradation of KDM4A, a histone demethylase (33), and seems to be involved in the inflammatory response during Salmonella infection (45). In its C-terminal region, FBXO22a has an F-box intracellular transduction C-terminal domain (FIST C), presumably involved in amino acid sensing and signal transduction (46).…”

Molecular Mechanisms Used by Salmonella to Evade the Immune System

“…This suggests that some Salmonella effector proteins could have a conserved function during proliferation in different hosts. GogB is another anti-inflammatory effector that limits NF-κB activation by targeting the host SCF E3 ubiquitin ligase and inhibiting IκBα degradation (Pilar et al, 2012). SseK1, an effector protein that can be secreted by T3SS1 and T3SS2 (Baisón-Olmo et al, 2015), has a N-acetylglucosamine transferase activity that modifies the TNF-α receptor TNFR1 and its adaptor TRADD, preventing TNF-α mediated activation of NF-κB (Li et al, 2013).…”