title: Fine-tuning nucleophosmin in macrophage differentiation and activation.
abstract: M-CSF-driven differentiation of peripheral blood monocytes is one of the sources of tissue macrophages. In humans and mice, the differentiation process involves the activation of caspases that cleave a limited number of proteins. One of these proteins is nucleophosmin (NPM1), a multifunctional and ubiquitous protein. Here, we show that caspases activated in monocytes exposed to M-CSF cleave NPM1 at D213 to generate a 30-kDa N-terminal fragment. The protein is further cleaved into a 20-kDa fragment, which involves cathepsin B. NPM1 fragments contribute to the limited motility, migration, and phagocytosis capabilities of resting macrophages. Their activation with lipopolysaccharides inhibits proteolytic processes and restores expression of the full-length protein that negatively regulates the transcription of genes encoding inflammatory cytokines (eg, NPM1 is recruited with NF-κB on the MCP1 gene promoter to decrease its transcription). In mice with heterozygous npm gene deletion, cytokine production in response to lipopolysaccharides, including CXCL1 (KC), MCP1, and MIP2, is dramatically enhanced. These results indicate a dual function of NPM1 in M-CSF-differentiated macrophages. Proteolysis of the protein participates in the establishment of a mature macrophage phenotype. In response to inflammatory stimuli, the full-length protein negatively regulates inflammatory cytokine production.
authors.affiliation: Inserm Unité Mixte de Recherche, Faculté de Médecine, Dijon, France.
authors.forename: Leslie
authors.initials: L
authors.lastname: Guery
authors.forename: Naïma
authors.initials: N
authors.lastname: Benikhlef
authors.forename: Thomas
authors.initials: T
authors.lastname: Gautier
authors.forename: Catherine
authors.initials: C
authors.lastname: Paul
authors.forename: Gaetan
authors.initials: G
authors.lastname: Jego
authors.forename: Erick
authors.initials: E
authors.lastname: Dufour
authors.forename: Arnaud
authors.initials: A
authors.lastname: Jacquel
authors.forename: Radj
authors.initials: R
authors.lastname: Cally
authors.forename: Bénédicte
authors.initials: B
authors.lastname: Manoury
authors.forename: Tom
authors.initials: T
authors.lastname: Vanden Berghe
authors.forename: Peter
authors.initials: P
authors.lastname: Vandenabeele
authors.forename: Nathalie
authors.initials: N
authors.lastname: Droin
authors.forename: Eric
authors.initials: E
authors.lastname: Solary
mesh_terms: D000818:Animals; D020169:Caspases / Q000378:metabolism; D002403:Cathepsins / Q000378:metabolism; D002454:Cell Differentiation / Q000187:drug effects / Q000235:genetics; D002478:Cells, Cultured; D006801:Humans; D008070:Lipopolysaccharides / Q000494:pharmacology; D008262:Macrophage Activation / Q000187:drug effects / Q000235:genetics / Q000502:physiology; D016173:Macrophage Colony-Stimulating Factor / Q000494:pharmacology; D008264:Macrophages / Q000187:drug effects / Q000378:metabolism / Q000502:physiology*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009687:Nuclear Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D000090243:Nucleophosmin; D011499:Protein Processing, Post-Translational / Q000187:drug effects; D017434:Protein Structure, Tertiary / Q000235:genetics / Q000502:physiology
chemical_list: D008070:Lipopolysaccharides; C000716967:NPM1 protein, human; C000715570:Npm1 protein, mouse; D009687:Nuclear Proteins; D000090243:Nucleophosmin; D016173:Macrophage Colony-Stimulating Factor; D002403:Cathepsins; D020169:Caspases