title: Targeting F box protein Fbxo3 to control cytokine-driven inflammation.
abstract: Cytokine-driven inflammation underlies the pathobiology of a wide array of infectious and immune-related disorders. The TNFR-associated factor (TRAF) proteins have a vital role in innate immunity by conveying signals from cell surface receptors to elicit transcriptional activation of genes encoding proinflammatory cytokines. We discovered that a ubiquitin E3 ligase F box component, termed Fbxo3, potently stimulates cytokine secretion from human inflammatory cells by mediating the degradation of the TRAF inhibitory protein, Fbxl2. Analysis of the Fbxo3 C-terminal structure revealed that the bacterial-like ApaG molecular signature was indispensible for mediating Fbxl2 disposal and stimulating cytokine secretion. By targeting this ApaG motif, we developed a highly unique, selective genus of small-molecule Fbxo3 inhibitors that by reducing TRAF protein levels, potently inhibited cytokine release from human blood mononuclear cells. The Fbxo3 inhibitors effectively lessened the severity of viral pneumonia, septic shock, colitis, and cytokine-driven inflammation systemically in murine models. Thus, pharmacological targeting of Fbxo3 might be a promising strategy for immune-related disorders characterized by a heightened host inflammatory response.
authors.affiliation: Division of Pulmonary, Allergy, and Critical Care Medicine, Department of Medicine, University of Pittsburgh, Pittsburgh, PA 15213;
authors.forename: Rama K
authors.initials: RK
authors.lastname: Mallampalli
authors.forename: Tiffany A
authors.initials: TA
authors.lastname: Coon
authors.forename: Jennifer R
authors.initials: JR
authors.lastname: Glasser
authors.forename: Claire
authors.initials: C
authors.lastname: Wang
authors.forename: Sarah R
authors.initials: SR
authors.lastname: Dunn
authors.forename: Nathaniel M
authors.initials: NM
authors.lastname: Weathington
authors.forename: Jing
authors.initials: J
authors.lastname: Zhao
authors.forename: Chunbin
authors.initials: C
authors.lastname: Zou
authors.forename: Yutong
authors.initials: Y
authors.lastname: Zhao
authors.forename: Bill B
authors.initials: BB
authors.lastname: Chen
mesh_terms: D000818:Animals; D001596:Benzylamines / Q000494:pharmacology / Q000627:therapeutic use*; D002460:Cell Line; D003092:Colitis / Q000188:drug therapy; D016207:Cytokines / Q000096:biosynthesis / Q000378:metabolism; D044783:F-Box Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism*; D007249:Inflammation / Q000188:drug therapy* / Q000276:immunology; D053118:Influenza A Virus, H1N1 Subtype / Q000187:drug effects; D007963:Leukocytes, Mononuclear / Q000187:drug effects / Q000276:immunology; D055370:Lung Injury / Q000188:drug therapy / Q000821:virology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009976:Orthomyxoviridae Infections / Q000188:drug therapy; D011725:Pyridines / Q000494:pharmacology / Q000627:therapeutic use*; D047988:Tumor Necrosis Factor Receptor-Associated Peptides and Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism*; D044767:Ubiquitin-Protein Ligases / Q000378:metabolism
chemical_list: C585582:BC-1215; D001596:Benzylamines; D016207:Cytokines; D044783:F-Box Proteins; C558726:FBXL2 protein, mouse; C585581:Fbxo3 protein, mouse; D011725:Pyridines; D047988:Tumor Necrosis Factor Receptor-Associated Peptides and Proteins; D044767:Ubiquitin-Protein Ligases