SseK1 and SseK3 T3SS effectors inhibit NF-kB signalling and necroptotic cell death in Salmonella-infected macrophages
File(s)
Published version
Author(s)
Gunster, R
Matthews, SA
Holden, DW
Thurston, T
Type
Journal Article
Abstract
Within host cells such as macrophages, Salmonella enterica translocates virulence (effector) proteins across its vacuolar membrane using the SPI-2 type III secretion system. Previously it has been shown that when expressed ectopically the effectors SseK1 and SseK3 inhibit TNFα-induced NF-κB activation. In this study we show that ectopically expressed SseK1, SseK2 and SseK3 suppressed TNFα-, but not TLR4-, or interleukin-induced NF-κB activation. Inhibition required a DXD motif, which in SseK1 and SseK3 is essential for protein Arginine-N-acetylglucosamine (GlcNAc)-ylation. During macrophage infection, SseK1 and SseK3 inhibited NF-κB activity in an additive manner. SseK3-mediated inhibition of NF-κB activation did not require the only known host-binding partner of this effector, the E3-ubiquitin ligase TRIM32. SseK proteins also inhibited TNFα-induced cell death during macrophage infection. Despite SseK1 and SseK3 inhibiting TNFα-induced apoptosis upon ectopic expression in HeLa cells, the percentage of infected macrophages undergoing apoptosis was SseK-independent. Instead, SseK proteins inhibited necroptotic cell death during macrophage infection. SseK1 and SseK3 caused GlcNAcylation of different proteins in infected macrophages suggesting that these effectors have distinct substrate specificities. Indeed, SseK1 caused the GlcNAcylation of the death domain containing proteins FADD and TRADD, whereas SseK3 expression resulted in weak GlcNAcylation of TRADD but not FADD. Additional, as yet unidentified substrates are likely to explain the additive phenotype of a Salmonella strain lacking both SseK1 and SseK3.
Date Issued
2017-01-09
Date Acceptance
2017-01-05
Citation
Infection and Immunity, 2017, 85 (3)
ISSN
1098-5522
Publisher
American Society for Microbiology
Journal / Book Title
Infection and Immunity
Volume
85
Issue
3
Copyright Statement
© 2017 Günster et al. This is an open-access article distributed under the terms of the Creative Commons Attribution 4.0 International license.
License URL
Sponsor
Wellcome Trust
Medical Research Council (MRC)
Wellcome Trust
Grant Number
095484/Z/11/Z
MR/K027077/1
097816/Z/11/B
Subjects
NF-κB signaling
Salmonella
cell death
necroptosis
Microbiology
06 Biological Sciences
11 Medical And Health Sciences
07 Agricultural And Veterinary Sciences
Publication Status
Published
Article Number
e00010-17