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

Artikel i vetenskaplig tidskrift
Författare Omar M. Khan
Mohamed X Ibrahim
Ing-Marie Jonsson
Christin Karlsson
Meng Liu
Anna-Karin Sjögren
Frida J Olofsson
Mikael Brisslert
Sofia E M Andersson
Claes Ohlsson
Lillemor Mattsson Hultén
Maria Bokarewa
Martin Bergö
Publicerad i The Journal of clinical investigation
Volym 121
Nummer/häfte 2
Sidor 628-39
ISSN 1558-8238
Publiceringsår 2011
Publicerad vid Wallenberglaboratoriet
Institutionen för medicin, avdelningen för reumatologi och inflammationsforskning
Institutionen för medicin
Institutionen för medicin, avdelningen för invärtesmedicin
Sidor 628-39
Språk en
Länkar dx.doi.org/10.1172/JCI43758
Ämnesord Alkyl and Aryl Transferases, deficiency, genetics, Animals, Arthritis, immunology, pathology, Cytokines, immunology, Macrophages, cytology, enzymology, immunology, physiology, Mice, Mice, Inbred C57BL, Mice, Knockout, cdc42 GTP-Binding Protein, genetics, metabolism, rac1 GTP-Binding Protein, genetics, metabolism, rap1 GTP-Binding Proteins, genetics, metabolism, rhoA GTP-Binding Protein, genetics, metabolism
Ämneskategorier Cellbiologi, Medicinsk cellbiologi

Sammanfattning

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.

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