Protein prenylation restrains innate immunity by inhibiting Rac1 effector interactions
| Autor: | Donghai Wang, Malin C. Erlandsson, Mohamed X. Ibrahim, Israiel T. Kumar, Christin Karlsson, Cord Brakebusch, Xiufeng Xu, Volkan I. Sayin, Maria Bokarewa, Omar M. Khan, Emil G. Ivarsson, Martin O. Bergo, Murali K. Akula, Mikael Brisslert |
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| Jazyk: | angličtina |
| Rok vydání: | 2019 |
| Předmět: |
rac1 GTP-Binding Protein
0301 basic medicine Mice 129 Strain RHOA Science Protein Prenylation General Physics and Astronomy Mice Transgenic RAC1 02 engineering and technology Signal transduction Article General Biochemistry Genetics and Molecular Biology Proinflammatory cytokine Mice 03 medical and health sciences Prenylation Animals lcsh:Science Innate immunity Inflammation Mice Knockout Alkyl and Aryl Transferases Multidisciplinary Innate immune system biology Chemistry Effector Macrophages Signal transducing adaptor protein General Chemistry 021001 nanoscience & nanotechnology Immunity Innate Cell biology Mice Inbred C57BL RAW 264.7 Cells 030104 developmental biology ras GTPase-Activating Proteins biology.protein Cytokines Protein prenylation lcsh:Q 0210 nano-technology Protein Binding |
| Zdroj: | Nature Communications, Vol 10, Iss 1, Pp 1-13 (2019) Nature Communications Akula, M K, Ibrahim, M X, Ivarsson, E G, Khan, O M, Kumar, I T, Erlandsson, M, Karlsson, C, Xu, X, Brisslert, M, Brakebusch, C, Wang, D, Bokarewa, M, Sayin, V I & Bergo, M O 2019, ' Protein prenylation restrains innate immunity by inhibiting Rac1 effector interactions ', Nature Communications, vol. 10, no. 1, 3975, pp. 1-13 . https://doi.org/10.1038/s41467-019-11606-x |
| ISSN: | 2041-1723 |
| DOI: | 10.1038/s41467-019-11606-x |
| Popis: | Rho family proteins are prenylated by geranylgeranyltransferase type I (GGTase-I), which normally target proteins to membranes for GTP-loading. However, conditional deletion of GGTase-I in mouse macrophages increases GTP-loading of Rho proteins, leading to enhanced inflammatory responses and severe rheumatoid arthritis. Here we show that heterozygous deletion of the Rho family gene Rac1, but not Rhoa and Cdc42, reverses inflammation and arthritis in GGTase-I-deficient mice. Non-prenylated Rac1 has a high affinity for the adaptor protein Ras GTPase-activating-like protein 1 (Iqgap1), which facilitates both GTP exchange and ubiquitination-mediated degradation of Rac1. Consistently, inactivating Iqgap1 normalizes Rac1 GTP-loading, and reduces inflammation and arthritis in GGTase-I-deficient mice, as well as prevents statins from increasing Rac1 GTP-loading and cytokine production in macrophages. We conclude that blocking prenylation stimulates Rac1 effector interactions and unleashes proinflammatory signaling. Our results thus suggest that prenylation normally restrains innate immune responses by preventing Rac1 effector interactions. Macrophage specific deletion of GGTase-I, a prenylation enzyme, in mice induces inflammatory response and rheumatoid arthritis. Here the authors show that GGTase-I deficiency and the resulting reduction of RAC1 prenylation increase RAC1 interaction with the adaptor protein IQGAP1, leading to GTP-loading of RAC1 and enhanced proinflammatory cytokine production. |
| Databáze: | OpenAIRE |
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