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Fine-tuning nucleophosmin in macrophage differentiation and activation

Inserm Unité Mixte de Recherche, Faculté de Médecine, Dijon, France.
Blood (Impact Factor: 10.43). 08/2011; 118(17):4694-704. DOI: 10.1182/blood-2011-03-341255
Source: PubMed

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.

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    • "with suc - cessive rounds of CSF - 1R Tyr - 723 phosphory - lation and dephosphorylation . Successive waves of Akt activation , increasing in amplitude and duration , are required for caspase activation , which , via cleavage of nucleophosmin , enhanc - es macrophage differentiation ( Jacquel et al . 2009 ) toward a trophic , M2 - like phenotype ( Guery et al . 2011 ) . Erk1 / 2 was activated with coordinated kinetics , but was not essential for nucleophosmin cleavage , and its role remains to be defined . In contrast , the SFKs , Hck , and , to a lesser extent , Lyn , but not Fyn or Src , medi - ated nucleophosmin cleavage downstream from CSF - 1R ( Jacquel et al . 2009 ) ."
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    • "NPM1 may also act as an alarmin in the immune system [44]. In macrophages, NPM1 negatively regulates cytokine and chemokine gene expression and their secretion [45]. We hypothesized that the NPM1 expression in tumor cells is modulated in response to microenvironmental stimuli. "
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    • "While the most commonly used proteasome inhibitor, MG132, is cheap and works well as a proteasome inhibitor for measuring chymotrypsin-like activity of the proteasome, it is not a good inhibitor for measuring the caspase-like or trypsin-like activity of the proteasome. MG132 is known to inhibit other proteases besides the proteasome including calpains [151] and cathepsins A, B, and K [152–154]. "
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