title: Shigella flexneri suppresses NF-κB activation by inhibiting linear ubiquitin chain ligation.
abstract: The linear ubiquitin chain assembly complex (LUBAC) is a multimeric E3 ligase that catalyses M1 or linear ubiquitination of activated immune receptor signalling complexes (RSCs). Mutations that disrupt linear ubiquitin assembly lead to complex disease pathologies including immunodeficiency and autoinflammation in both humans and mice, but microbial toxins that target LUBAC function have not yet been discovered. Here, we report the identification of two homologous Shigella flexneri type III secretion system effector E3 ligases IpaH1.4 and IpaH2.5, which directly interact with LUBAC subunit Heme-oxidized IRP2 ubiquitin ligase-1 (HOIL-1L) and conjugate K48-linked ubiquitin chains to the catalytic RING-between-RING domain of HOIL-1-interacting protein (HOIP). Proteasomal degradation of HOIP leads to irreversible inactivation of linear ubiquitination and blunting of NF-κB nuclear translocation in response to tumour-necrosis factor (TNF), IL-1β and pathogen-associated molecular patterns. Loss of function studies in mammallian cells in combination with bacterial genetics explains how Shigella evades a broad spectrum of immune surveillance systems by cooperative inhibition of receptor ubiquitination and reveals the critical importance of LUBAC in host defence against pathogens.
authors: Department of Microbiology, University of Texas Southwestern Medical Center, Dallas, Texas 75390, USA.
authors: Maarten F
authors: MF
authors: de Jong
authors: Department of Microbiology, University of Texas Southwestern Medical Center, Dallas, Texas 75390, USA.
authors: Zixu
authors: Z
authors: Liu
authors: Department of Microbiology, University of Texas Southwestern Medical Center, Dallas, Texas 75390, USA.
authors: Didi
authors: D
authors: Chen
authors: Department of Microbiology, University of Texas Southwestern Medical Center, Dallas, Texas 75390, USA.
authors: Neal M
authors: NM
authors: Alto
mesh_terms: D000818:Animals; D005786:Gene Expression Regulation; D006801:Humans; D057131:Immune Evasion; D007113:Immunity, Innate; D053583:Interleukin-1beta / Q000276:immunology / Q000378:metabolism; D051379:Mice; D016328:NF-kappa B / Q000378:metabolism*; D012763:Shigella flexneri / Q000276:immunology / Q000378:metabolism* / Q000472:pathogenicity; D015398:Signal Transduction; D014409:Tumor Necrosis Factor-alpha / Q000276:immunology; D000069296:Type III Secretion Systems; D025801:Ubiquitin / Q000235:genetics / Q000378:metabolism*; D044767:Ubiquitin-Protein Ligases / Q000235:genetics / Q000378:metabolism; D054875:Ubiquitination
chemical_list: D053583:Interleukin-1beta; D016328:NF-kappa B; D014409:Tumor Necrosis Factor-alpha; D000069296:Type III Secretion Systems; D025801:Ubiquitin; C558338:RNF31 protein, human; D044767:Ubiquitin-Protein Ligases