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The Golgi-associated protein p115 mediates the secretion of macrophage migration inhibitory factor
Melanie Merk1, John Baugh, Swen Zierow
1Yale University School of Medicine, New Haven, CT 06520, USA.
Abstract:
Macrophage migration inhibitory factor (MIF) is a leaderless protein that is secreted from cells by a specialized, nonclassical export pathway. The release of MIF nevertheless is regulated and its production in response to different inflammatory, mitogenic, and hormonal stimuli plays an important role in diverse physiologic and pathologic processes. We report herein the identification of the Golgi complex-associated protein p115 as an intracellular binding partner for MIF. MIF interacts with p115 in the cytoplasm and the stimulated secretion of MIF results in the accumulation of both proteins in supernatants, which is consistent with MIF release from cells in conjunction with p115. The depletion of p115 from monocytes/macrophages decreases the release of MIF but not other cytokines following inflammatory stimulation or intracellular bacterial infection. Notably, the small molecule MIF inhibitor 4-iodo-6-phenylpyrimidine inhibits MIF secretion by targeting the interaction between MIF and p115. These data reveal p115 to be a critical intermediary component in the regulated secretion of MIF from monocytes/macrophages.
Insights
Macrophage migration inhibitory factor (MIF) secretion involves the Golgi-associated protein p115. This protein is crucial for MIF release from monocytes and macrophages, impacting inflammatory responses.
Area of Science:
- Cell Biology
- Immunology
- Molecular Biology
Background:
- Macrophage migration inhibitory factor (MIF) is a leaderless protein secreted via a nonclassical pathway.
- MIF release is regulated and plays a role in inflammatory, mitogenic, and hormonal processes.
Purpose of the Study:
- To identify intracellular binding partners of MIF involved in its secretion.
- To elucidate the role of identified partners in MIF release from monocytes/macrophages.
Main Methods:
- Co-immunoprecipitation to identify MIF binding partners.
- Protein depletion studies (p115 knockdown) in monocytes/macrophages.
- Analysis of cytokine release following inflammatory stimulation and bacterial infection.
- Assessment of MIF inhibitor efficacy on MIF-p115 interaction.
Main Results:
- Golgi complex-associated protein p115 identified as an intracellular MIF binding partner.
- MIF and p115 co-accumulate in cell supernatants upon stimulated secretion.
- p115 depletion reduces MIF release but not other cytokines.
- A small molecule MIF inhibitor targets the MIF-p115 interaction to inhibit MIF secretion.
Conclusions:
- p115 is a critical intermediary in the regulated secretion of MIF from monocytes/macrophages.
- Targeting the MIF-p115 interaction offers a potential therapeutic strategy for modulating MIF secretion.
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