Dendritic Cell IL-1α and IL-1β Are Polyubiquitinated and Degraded by the Proteasome

• Published in: The Journal of biological chemistry Vol. 289; no. 51; pp. 35582 - 35592
• Main Authors: Ainscough, Joseph S., Frank Gerberick, G., Zahedi-Nejad, Maryam, Lopez-Castejon, Gloria, Brough, David, Kimber, Ian, Dearman, Rebecca J.
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 19.12.2014; American Society for Biochemistry and Molecular Biology
• Subjects: Animals; Blotting, Western; Bone Marrow Cells - drug effects; Bone Marrow Cells - metabolism; Cells, Cultured; Cysteine Proteinase Inhibitors - pharmacology; Dendritic Cell; Dendritic Cells - drug effects; Dendritic Cells - metabolism; Female; IL-1α IL-1β; Immunology; Inflammation; Interleukin 1 (IL-1); Interleukin-1 - genetics; Interleukin-1 - metabolism; Interleukin-1alpha - genetics; Interleukin-1alpha - metabolism; Interleukin-1beta - genetics; Interleukin-1beta - metabolism; Leupeptins - pharmacology; Lipopolysaccharides - pharmacology; Macrophages - drug effects; Macrophages - metabolism; Mice, Inbred BALB C; Polyubiquitin - metabolism; Proteasome; Proteasome Endopeptidase Complex - metabolism; Protein Precursors - genetics; Protein Precursors - metabolism; Proteolysis - drug effects; Reverse Transcriptase Polymerase Chain Reaction; Ubiquitination - drug effects; Ubiquitylation (Ubiquitination); Interleukin 1 (IL-1); Inflammation; Ubiquitylation (Ubiquitination); IL-1α IL-1β; Dendritic Cell; Proteasome
• ISSN: 0021-9258; 1083-351X; 1083-351X
• DOI: 10.1074/jbc.M114.595686

IL-1α and β are key players in the innate immune system. The secretion of these cytokines by dendritic cells (DC) is integral to the development of proinflammatory responses. These cytokines are not secreted via the classical secretory pathway. Instead, 2 independent processes are required; an initial signal to induce up-regulation of the precursor pro-IL-1α and -β, and a second signal to drive cleavage and consequent secretion. Pro-IL-1α and -β are both cytosolic and thus, are potentially subject to post-translational modifications. These modifications may, in turn, have a functional outcome in the context of IL-1α and -β secretion and hence inflammation. We report here that IL-1α and -β were degraded intracellularly in murine bone marrow-derived DC and that this degradation was dependent on active cellular processes. In addition, we demonstrate that degradation was ablated when the proteasome was inhibited, whereas autophagy did not appear to play a major role. Furthermore, inhibition of the proteasome led to an accumulation of polyubiquitinated IL-1α and -β, indicating that IL-1α and -β were polyubiquitinated prior to proteasomal degradation. Finally, our investigations suggest that polyubiquitination and proteasomal degradation are not continuous processes but instead are up-regulated following DC activation. Overall, these data highlight that IL-1α and -β polyubiquitination and proteasomal degradation are central mechanisms in the regulation of intracellular IL-1 levels in DC. Background: Interleukin-1 secretion is an important process in inflammation and thus, the intracellular regulation of these cytokines is of interest. Results: Inhibition of the proteasome in dendritic cells inhibits interleukin-1 degradation and leads to an accumulation of polyubiquitinated interleukin-1. Conclusion: Interleukin-1 cytokines are regulated by polyubiquitination and proteasomal degradation. Significance: Polyubiquitination and degradation are important processes in the intracellular regulation of interleukin-1.