title: Bacterial E3 Ubiquitin Ligase IpaH4.5 of Shigella flexneri Targets TBK1 To Dampen the Host Antibacterial Response.
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.
authors.affiliation: State Key Laboratory of Pathogen and Biosecurity, Beijing Institute of Biotechnology, Beijing 100850, People's Republic of China;
authors.forename: Zirui
authors.initials: Z
authors.lastname: Zheng
authors.affiliation: State Key Laboratory of Pathogen and Biosecurity, Beijing Institute of Biotechnology, Beijing 100850, People's Republic of China;
authors.forename: Congwen
authors.initials: C
authors.lastname: Wei
authors.affiliation: State Key Laboratory of Pathogen and Biosecurity, Beijing Institute of Biotechnology, Beijing 100850, People's Republic of China;
authors.forename: Kai
authors.initials: K
authors.lastname: Guan
authors.affiliation: Central Laboratory of Binhu Hospital, The Third Affiliated Hospital of Anhui Medical University, Hefei 230601, People's Republic of China; and.
authors.forename: Yuan
authors.initials: Y
authors.lastname: Yuan
authors.affiliation: State Key Laboratory of Pathogen and Biosecurity, Beijing Institute of Biotechnology, Beijing 100850, People's Republic of China;
authors.forename: Yanhong
authors.initials: Y
authors.lastname: Zhang
authors.affiliation: State Key Laboratory of Pathogen and Biosecurity, Beijing Institute of Biotechnology, Beijing 100850, People's Republic of China;
authors.forename: Shengli
authors.initials: S
authors.lastname: Ma
authors.affiliation: State Key Laboratory of Pathogen and Biosecurity, Beijing Institute of Biotechnology, Beijing 100850, People's Republic of China;
authors.forename: Ye
authors.initials: Y
authors.lastname: Cao
authors.affiliation: Center for Hospital Infection Control, The 309th Hospital of Chinese People's Liberation Army, Beijing 100091, People's Republic of China.
authors.forename: Fang
authors.identifier: http://orcid.org/0000-0002-9024-4628
authors.initials: F
authors.lastname: Wang
authors.affiliation: State Key Laboratory of Pathogen and Biosecurity, Beijing Institute of Biotechnology, Beijing 100850, People's Republic of China;
authors.forename: Hui
authors.initials: H
authors.lastname: Zhong
authors.affiliation: State Key Laboratory of Pathogen and Biosecurity, Beijing Institute of Biotechnology, Beijing 100850, People's Republic of China; hexiang_spring@yahoo.com.
authors.forename: Xiang
authors.initials: X
authors.lastname: He
mesh_terms: D000818:Animals; D000942:Antigens, Bacterial / Q000276:immunology / Q000378:metabolism*; D001426:Bacterial Proteins / Q000276:immunology / Q000378:metabolism*; D002460:Cell Line; D004405:Dysentery, Bacillary / Q000276:immunology / Q000378:metabolism*; D057809:HEK293 Cells; D006367:HeLa Cells; D006790:Host-Parasite Interactions / Q000502:physiology*; D006801:Humans; D015151:Immunoblotting; D047468:Immunoprecipitation; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D017346:Protein Serine-Threonine Kinases / Q000276:immunology / Q000378:metabolism*; D060888:Real-Time Polymerase Chain Reaction; D014162:Transfection
chemical_list: D000942:Antigens, Bacterial; D001426:Bacterial Proteins; C063500:ipaH protein, Shigella flexneri; D017346:Protein Serine-Threonine Kinases; C403191:TBK1 protein, human