ArticleThe Journal of clinical investigation2011
Geranylgeranyltransferase type I (GGTase-I) deficiency hyperactivates macrophages and induces erosive arthritis in mice.
Article in The Journal of clinical investigation, 2011. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 62 papers.
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Who cites it
62 citing papers in PubMed, 111 citations in OpenAlex.
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- Metabolic signature and proteasome activity controls synovial migration ofFrontiers in immunology · 2023Article
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- Cholesterol metabolism: a new molecular switch to control inflammation.Clinical science (London, England : 1979) · 2021Review
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- Compromised Protein Prenylation as Pathogenic Mechanism in Mevalonate Kinase Deficiency.Frontiers in immunology · 2021Review
- SmgGDS: An Emerging Master Regulator of Prenylation and Trafficking by Small GTPases in the Ras and Rho Families.Frontiers in molecular biosciences · 2021Review
- A Requirement of Protein Geranylgeranylation for Chemokine Receptor Signaling and Th17 Cell Function in an Animal Model of Multiple Sclerosis.Frontiers in immunology · 2021Article
- Role of Macrophages and RhoA Pathway in Atherosclerosis.International journal of molecular sciences · 2020Review
- Scaffold association factor B (SAFB) is required for expression of prenyltransferases and RAS membrane association.Proceedings of the National Academy of Sciences of the United States of America · 2020Article
2 more citing papers are in PubMed but not listed here.
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Authors and funding
13 authors at 2 institutions in 2 countries.
Funding
No grant is acknowledged in the PubMed record.
Abstract
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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