Interleukin-1ß Processing Is Dependent on a Calcium-mediated Interaction with Calmodulin.
J Biol Chem
; 290(52): 31151-61, 2015 Dec 25.
Article
em En
| MEDLINE
| ID: mdl-26559977
ABSTRACT
The secretion of IL-1ß is a central event in the initiation of inflammation. Unlike most other cytokines, the secretion of IL-1ß requires two signals one signal to induce the intracellular up-regulation of pro-IL-1ß and a second signal to drive secretion of the bioactive molecule. The release of pro-IL-1ß is a complex process involving proteolytic cleavage by caspase-1. However, the exact mechanism of secretion is poorly understood. Here we sought to identify novel proteins involved in IL-1ß secretion and intracellular processing to gain further insights into the mechanism of IL-1 release. A human proteome microarray containing 19,951 unique proteins was used to identify proteins that bind human recombinant pro-IL-1ß. Probes with a signal-to-noise ratio of >3 were defined as biologically relevant. In these analyses, calmodulin was identified as a particularly strong hit, with a signal-to-noise ratio of â¼ 11. Using an ELISA-based protein-binding assay, the interaction of recombinant calmodulin with pro-IL-1ß, but not mature IL-1ß, was confirmed and shown to be calcium-dependent. Finally, using small molecule inhibitors, it was demonstrated that both calcium and calmodulin were required for nigericin-induced IL-1ß secretion in THP-1 cells and primary human monocytes. Together, these data suggest that, following calcium influx into the cell, pro-IL-1ß interacts with calmodulin and that this interaction is important for IL-1ß processing and release.
Palavras-chave
Texto completo:
1
Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Precursores de Proteínas
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Calmodulina
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Monócitos
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Cálcio
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Sinalização do Cálcio
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Interleucina-1beta
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Proteólise
Tipo de estudo:
Prognostic_studies
Limite:
Female
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Humans
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Male
Idioma:
En
Revista:
J Biol Chem
Ano de publicação:
2015
Tipo de documento:
Article