PMID:26700764

Citation	Zheng, Z, Wei, C, Guan, K, Yuan, Y, Zhang, Y, Ma, S, Cao, Y, Wang, F, Zhong, H and He, X (2016) Bacterial E3 Ubiquitin Ligase IpaH4.5 of Shigella flexneri Targets TBK1 To Dampen the Host Antibacterial Response. J. Immunol. 196:1199-208
Abstract	IFN regulatory factors play a pivotal role in many cellular processes, including inflammatory and immune responses. Their activation is tightly regulated by TANK-binding kinase 1 (TBK1). In response to microbial components, TBK1 activates IFN regulatory factor 3 (IRF3) and cytokine expression. In this article, we show that TBK1 is a novel target of the IpaH4.5 protein, a Shigella type III effector possessing E3 ubiquitin ligase activity. Remarkably, IpaH4.5 interacts with TBK1 and promotes its K48-linked polyubiquitylation. Consequently, polyubiquitylated TBK1 undergoes proteasome-dependent degradation, which perturbs the phosphorylation, nuclear translocation, and activation of IRF3. Because IRF3 and TBK1 are required for restricting Shigella growth, we propose that the polyubiquitylation and degradation of TBK1 during Shigella infection are new bacterial strategies to modulate the host antibacterial responses.
Links	PubMed Online version:10.4049/jimmunol.1501045
Keywords	Animals; Antigens, Bacterial/immunology; Antigens, Bacterial/metabolism; Bacterial Proteins/immunology; Bacterial Proteins/metabolism; Cell Line; Dysentery, Bacillary/immunology; Dysentery, Bacillary/metabolism; HEK293 Cells; HeLa Cells; Host-Parasite Interactions/physiology; Humans; Immunoblotting; Immunoprecipitation; Male; Mice; Mice, Inbred C57BL; Protein-Serine-Threonine Kinases/immunology; Protein-Serine-Threonine Kinases/metabolism; Real-Time Polymerase Chain Reaction; Transfection
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Annotations

Gene product	Qualifier	GO Term	Evidence Code	with/from	Aspect	Extension	Notes	Status
SHIFL:IPA4		GO:0052170: negative regulation by symbiont of host innate immune response	ECO:0000315:		P		Shigella flexneri Figure 1A and 1B show that the IPA4 lowers IRF3 activity which is a vital component of host immune response. The delta IPA4, inversely, shows an increase in IRF3 activity in figure 1B which is expected if IPA4 negatively regulates host immune response	complete CACAO 12966
SHIFL:IPA4		GO:0006511: ubiquitin-dependent protein catabolic process	ECO:0000315: mutant phenotype evidence used in manual assertion		P		Shigella flexneri Protein is IPA4 but referred to as IPAH4.5 in paper. Figure 5A-E: "The results showed that TBK1 was ubiquitylated in vitro by IpaH4.5" and Figure 5A-E show that "paH4.5 induces TBK1 degradation by K48-linked ubiquitination"	complete CACAO 12967

References

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