Arg-GlcNAcylation on TRADD by NleB and SseK1 Is Crucial for Bacterial Pathogenesis.

Juan Xue,Qi Zhang,Shufan Hu,Xing Pan,Shan Li,Xueying Yi,Yuxuan Huang

doi:10.3389/fcell.2020.00641

Abstract

Death receptor signaling is critical for cell death, inflammation, and immune homeostasis. Hijacking death receptors and their corresponding adaptors through type III secretion system (T3SS) effectors has been evolved to be a bacterial evasion strategy. NleB from enteropathogenic Escherichia coli (EPEC) and SseK1/2/3 from Salmonella enterica serovar Typhimurium (S. Typhimurium) can modify some death domain (DD) proteins through arginine-GlcNAcylation. Here, we performed a substrate screen on 12 host DD proteins with conserved arginine during EPEC and Salmonella infection. NleB from EPEC hijacked death receptor signaling through tumor necrosis factor receptor 1 (TNFR1)-associated death domain protein (TRADD), FAS-associated death domain protein (FADD), and receptor-interacting serine/threonine-protein kinase 1 (RIPK1), whereas SseK1 and SseK3 disturbed TNF signaling through the modification of TRADD Arg235/Arg245 and TNFR1 Arg376, respectively. Furthermore, mouse infection studies showed that SseK1 but not SseK3 rescued the bacterial colonization deficiency contributed by the deletion of NleBc (Citrobacter NleB), indicating that TRADD was the in vivo substrate. The result provides an insight into the mechanism by which attaching and effacing (A/E) pathogen manipulate TRADD-mediated signaling and evade host immune defense through T3SS effectors.

Highlights

Death receptor signaling is crucial for cell death (Giogha et al, 2014; Luo et al, 2015; Galluzzi et al, 2018), inflammation (Park et al, 2007), and immune homeostasis (Wilson et al, 2009)
The TRADD−/− mice infection model confirmed this result. All these findings suggest that arginine GlcNAcylation in TRADD catalyzed by type III-translocated bacterial effector proteins NleB and SseK1 is crucial for the pathogenesis of A/E pathogen
Previous studies confirmed that the arginine GlcNAc transferase activity of NleB was essential for bacterial colonization in the mouse model of enteropathogenic Escherichia coli (EPEC) infection (Li et al, 2013; Pearson et al, 2013; Ding et al, 2019)

Summary

Introduction

Death receptor signaling is crucial for cell death (Giogha et al, 2014; Luo et al, 2015; Galluzzi et al, 2018), inflammation (Park et al, 2007), and immune homeostasis (Wilson et al, 2009) It is mediated by homotypic or heterotypic interactions among death domains (DDs) of the TNFR family of transmembrane death receptors and the downstream adaptors, including TRADD (Hsu et al, 1995; Luo et al, 2015), RIPK1 (Stanger et al, 1995; Luo et al, 2015), and FADD (Chinnaiyan et al, 1995; Luo et al, 2015). Modification of TRADD, FADD, and RIPK1 in in vitro reconstitution system and ex vivo epithelial cell infection system has been studied, the in vivo substrate preference of NleB remains elusive

Methods

Results

Conclusion