A Marine Diterpenoid Modulates the Proteasome Activity in Murine Macrophages Stimulated with LPS
The proteasome is an intracellular complex that degrades damaged or unfolded proteins and participates in the regulation of several processes. The immunoproteasome is a specialized form that is expressed in response to proinflammatory signals and is particularly abundant in immune cells. In a previo...
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MDPI AG
2018-10-01
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| Series: | Biomolecules |
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| Online Access: | http://www.mdpi.com/2218-273X/8/4/109 |
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| author | Yisett González Deborah Doens Héctor Cruz Ricardo Santamaría Marcelino Gutiérrez Alejandro Llanes Patricia L. Fernández |
| author_facet | Yisett González Deborah Doens Héctor Cruz Ricardo Santamaría Marcelino Gutiérrez Alejandro Llanes Patricia L. Fernández |
| author_sort | Yisett González |
| collection | DOAJ |
| description | The proteasome is an intracellular complex that degrades damaged or unfolded proteins and participates in the regulation of several processes. The immunoproteasome is a specialized form that is expressed in response to proinflammatory signals and is particularly abundant in immune cells. In a previous work, we found an anti-inflammatory effect in a diterpenoid extracted from the octocoral Pseudopterogorgia acerosa, here called compound 1. This compound prevented the degradation of inhibitor κB α (IκBα) and the subsequent activation of nuclear factor κB (NFκB), suggesting that this effect might be due to inhibition of the ubiquitin-proteasome system. Here we show that compound 1 inhibits the proteasomal chymotrypsin-like activity (CTL) of murine macrophages in the presence of lipopolysaccharide (LPS) but not in its absence. This effect might be due to the capacity of this compound to inhibit the activity of purified immunoproteasome. The compound inhibits the cell surface expression of major histocompatibility complex (MHC)-I molecules and the production of proinflammatory cytokines induced by LPS in vitro and in vivo, respectively. Molecular docking simulations predicted that compound 1 selectively binds to the catalytic site of immunoproteasome subunits β1i and β5i, which are responsible for the CTL activity. Taken together these findings suggest that the compound could be a selective inhibitor of the immunoproteasome, and hence could pave the way for its future evaluation as a candidate for the treatment of inflammatory disorders and autoimmune diseases. |
| first_indexed | 2024-12-21T12:27:05Z |
| format | Article |
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| institution | Directory Open Access Journal |
| issn | 2218-273X |
| language | English |
| last_indexed | 2024-12-21T12:27:05Z |
| publishDate | 2018-10-01 |
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| series | Biomolecules |
| spelling | doaj.art-34ba1b471c3c4187af7d43f646650fe32022-12-21T19:04:09ZengMDPI AGBiomolecules2218-273X2018-10-018410910.3390/biom8040109biom8040109A Marine Diterpenoid Modulates the Proteasome Activity in Murine Macrophages Stimulated with LPSYisett González0Deborah Doens1Héctor Cruz2Ricardo Santamaría3Marcelino Gutiérrez4Alejandro Llanes5Patricia L. Fernández6Centro de Biología Celular y Molecular de Enfermedades, Instituto de Investigaciones Científicas y Servicios de Alta Tecnología (INDICASAT AIP),Edificio 219, Ciudad del Saber, 0801 Panamá, PanamáCentro de Biología Celular y Molecular de Enfermedades, Instituto de Investigaciones Científicas y Servicios de Alta Tecnología (INDICASAT AIP),Edificio 219, Ciudad del Saber, 0801 Panamá, PanamáCentro de Biología Celular y Molecular de Enfermedades, Instituto de Investigaciones Científicas y Servicios de Alta Tecnología (INDICASAT AIP),Edificio 219, Ciudad del Saber, 0801 Panamá, PanamáCentro de Biodiversidad y Descubrimiento de Drogas, INDICASAT AIP, Edificio 219, Ciudad del Saber, 0801 Panamá, PanamáCentro de Biodiversidad y Descubrimiento de Drogas, INDICASAT AIP, Edificio 219, Ciudad del Saber, 0801 Panamá, PanamáCentro de Biología Celular y Molecular de Enfermedades, Instituto de Investigaciones Científicas y Servicios de Alta Tecnología (INDICASAT AIP),Edificio 219, Ciudad del Saber, 0801 Panamá, PanamáCentro de Biología Celular y Molecular de Enfermedades, Instituto de Investigaciones Científicas y Servicios de Alta Tecnología (INDICASAT AIP),Edificio 219, Ciudad del Saber, 0801 Panamá, PanamáThe proteasome is an intracellular complex that degrades damaged or unfolded proteins and participates in the regulation of several processes. The immunoproteasome is a specialized form that is expressed in response to proinflammatory signals and is particularly abundant in immune cells. In a previous work, we found an anti-inflammatory effect in a diterpenoid extracted from the octocoral Pseudopterogorgia acerosa, here called compound 1. This compound prevented the degradation of inhibitor κB α (IκBα) and the subsequent activation of nuclear factor κB (NFκB), suggesting that this effect might be due to inhibition of the ubiquitin-proteasome system. Here we show that compound 1 inhibits the proteasomal chymotrypsin-like activity (CTL) of murine macrophages in the presence of lipopolysaccharide (LPS) but not in its absence. This effect might be due to the capacity of this compound to inhibit the activity of purified immunoproteasome. The compound inhibits the cell surface expression of major histocompatibility complex (MHC)-I molecules and the production of proinflammatory cytokines induced by LPS in vitro and in vivo, respectively. Molecular docking simulations predicted that compound 1 selectively binds to the catalytic site of immunoproteasome subunits β1i and β5i, which are responsible for the CTL activity. Taken together these findings suggest that the compound could be a selective inhibitor of the immunoproteasome, and hence could pave the way for its future evaluation as a candidate for the treatment of inflammatory disorders and autoimmune diseases.http://www.mdpi.com/2218-273X/8/4/109marine diterpenoidproteasome inhibitorsimmunoproteasome |
| spellingShingle | Yisett González Deborah Doens Héctor Cruz Ricardo Santamaría Marcelino Gutiérrez Alejandro Llanes Patricia L. Fernández A Marine Diterpenoid Modulates the Proteasome Activity in Murine Macrophages Stimulated with LPS Biomolecules marine diterpenoid proteasome inhibitors immunoproteasome |
| title | A Marine Diterpenoid Modulates the Proteasome Activity in Murine Macrophages Stimulated with LPS |
| title_full | A Marine Diterpenoid Modulates the Proteasome Activity in Murine Macrophages Stimulated with LPS |
| title_fullStr | A Marine Diterpenoid Modulates the Proteasome Activity in Murine Macrophages Stimulated with LPS |
| title_full_unstemmed | A Marine Diterpenoid Modulates the Proteasome Activity in Murine Macrophages Stimulated with LPS |
| title_short | A Marine Diterpenoid Modulates the Proteasome Activity in Murine Macrophages Stimulated with LPS |
| title_sort | marine diterpenoid modulates the proteasome activity in murine macrophages stimulated with lps |
| topic | marine diterpenoid proteasome inhibitors immunoproteasome |
| url | http://www.mdpi.com/2218-273X/8/4/109 |
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