Geranylgeranyltransferase type I (GGTase-I) deficiency hyperactivates macrophages and induces erosive arthritis in mice

• Published in: The Journal of clinical investigation Vol. 121; no. 2; pp. 628 - 639
• Main Authors: Khan, Omar M, Ibrahim, Mohamed X, Jonsson, Ing-Marie, Karlsson, Christin, Liu, Meng, Sjogren, Anna-Karin M, Olofsson, Frida J, Brisslert, Mikael, Andersson, Sofia, Ohlsson, Claes, Hultén, Lillemor Mattsson, Bokarewa, Maria, Bergo, Martin O
• Format: Journal Article
• Language: English
• Published: United States American Society for Clinical Investigation 01.02.2011
• Subjects: Alkyl and Aryl Transferases; Alkyl and Aryl Transferases - deficiency; Alkyl and Aryl Transferases - genetics; Animals; Arthritis; Arthritis - immunology; Arthritis - pathology; Autoimmune diseases; Biomedical research; Carbon; cdc42 GTP-Binding Protein; cdc42 GTP-Binding Protein - genetics; cdc42 GTP-Binding Protein - metabolism; Cell and Molecular Biology; Cell- och molekylärbiologi; Cytokines; Cytokines - immunology; cytology; deficiency; enzymology; genetics; immunology; Inbred C57BL; Inflammation; Inflammatory diseases; Knockout; Lipids; Lymphocytes; Macrophages; Macrophages - cytology; Macrophages - enzymology; Macrophages - immunology; Macrophages - physiology; metabolism; Mice; Mice, Inbred C57BL; Mice, Knockout; Neutrophils; pathology; Physiological aspects; physiology; Proteins; rac1 GTP-Binding Protein; rac1 GTP-Binding Protein - genetics; rac1 GTP-Binding Protein - metabolism; rap1 GTP-Binding Proteins; rap1 GTP-Binding Proteins - genetics; rap1 GTP-Binding Proteins - metabolism; Rheumatoid arthritis; Rheumatoid factor; rhoA GTP-Binding Protein; rhoA GTP-Binding Protein - genetics; rhoA GTP-Binding Protein - metabolism; Risk factors; Statins; Transferases; Sweden
• ISSN: 0021-9738; 1558-8238; 1558-8238
• DOI: 10.1172/JCI43758

RHO family proteins are important for the function of inflammatory cells. They are modified with a 20-carbon geranylgeranyl lipid in a process catalyzed by protein geranylgeranyltransferase type I (GGTase-I). Geranylgeranylation is viewed as essential for the membrane targeting and activity of RHO proteins. Consequently, inhibiting GGTase-I to interfere with RHO protein activity has been proposed as a strategy to treat inflammatory disorders. However, here we show that mice lacking GGTase-I in macrophages develop severe joint inflammation resembling erosive rheumatoid arthritis. The disease was initiated by the GGTase-I-deficient macrophages and was transplantable and reversible in bone marrow transplantation experiments. The cells accumulated high levels of active GTP-bound RAC1, CDC42, and RHOA, and RAC1 remained associated with the plasma membrane. Moreover, GGTase-I deficiency activated p38 and NF-κB and increased the production of proinflammatory cytokines. The results challenge the view that geranylgeranylation is essential for the activity and localization of RHO family proteins and suggest that reduced geranylgeranylation in macrophages can initiate erosive arthritis.