title: An IκB Kinase-Regulated Feedforward Circuit Prolongs Inflammation.
abstract: Loss of NF-κB signaling causes immunodeficiency, whereas inhibition of NF-κB can be efficacious in treating chronic inflammatory disease. Inflammatory NF-κB signaling must therefore be tightly regulated, and although many mechanisms to downregulate NF-κB have been elucidated, there have only been limited studies demonstrating positive feedforward regulation of NF-κB signaling. In this work, we use a bioinformatic and proteomic approach to discover that the IKK family of proteins can phosphorylate the E3 ubiquitin ligase ITCH, a critical downregulator of TNF-mediated NF-κB activation. Phosphorylation of ITCH by IKKs leads to impaired ITCH E3 ubiquitin ligase activity and prolongs NF-κB signaling and pro-inflammatory cytokine release. Since genetic loss of ITCH mirrors IKK-induced ITCH phosphorylation, we further show that the ITCH(-/-) mouse's spontaneous lung inflammation and subsequent death can be delayed when TNF signaling is genetically deleted. This work identifies a new positive feedforward regulation of NF-κB activation that drives inflammatory disease.
authors.affiliation: Department of Pathology, Case Western Reserve University (CWRU) School of Medicine, Cleveland, OH 44106, USA.
authors.forename: Jessica M
authors.initials: JM
authors.lastname: Perez
authors.affiliation: Department of Pathology, Case Western Reserve University (CWRU) School of Medicine, Cleveland, OH 44106, USA.
authors.forename: Steven M
authors.initials: SM
authors.lastname: Chirieleison
authors.affiliation: Department of Pathology, Case Western Reserve University (CWRU) School of Medicine, Cleveland, OH 44106, USA. Electronic address: dwa4@case.edu.
authors.forename: Derek W
authors.initials: DW
authors.lastname: Abbott
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D005246:Feedback; D057809:HEK293 Cells; D006801:Humans; D051550:I-kappa B Kinase / Q000378:metabolism*; D007249:Inflammation / Q000378:metabolism; D019169:Jurkat Cells; D008168:Lung / Q000378:metabolism / Q000473:pathology; D051379:Mice; D008810:Mice, Inbred C57BL; D008969:Molecular Sequence Data; D016328:NF-kappa B / Q000378:metabolism; D017434:Protein Structure, Tertiary; D015290:Second Messenger Systems; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism; D044767:Ubiquitin-Protein Ligases / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*
chemical_list: D016328:NF-kappa B; D014409:Tumor Necrosis Factor-alpha; C471637:Itch protein, mouse; D044767:Ubiquitin-Protein Ligases; D051550:I-kappa B Kinase