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Protein prenylation restrains innate immunity by inhibiting Rac1 effector interactions

Akula, Murali K (author)
Gothenburg University,Göteborgs universitet,Sahlgrenska Cancer Center,Wallenberg Centre for Molecular and Translational Medicine,Institutionen för medicin, avdelningen för molekylär och klinisk medicin,Institute of Medicine, Department of Molecular and Clinical Medicine
Ibrahim, Mohamed X (author)
Gothenburg University,Göteborgs universitet,Institutionen för medicin, avdelningen för molekylär och klinisk medicin,Sahlgrenska Cancer Center,Institute of Medicine, Department of Molecular and Clinical Medicine
Ivarsson, Emil G., 1989 (author)
Gothenburg University,Göteborgs universitet,Sahlgrenska Cancer Center,Institutionen för medicin, avdelningen för molekylär och klinisk medicin,Institute of Medicine, Department of Molecular and Clinical Medicine
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Khan, O. M. (author)
Kumar, Israiel T. (author)
Gothenburg University,Göteborgs universitet,Institutionen för medicin, avdelningen för molekylär och klinisk medicin,Sahlgrenska Cancer Center,Institute of Medicine, Department of Molecular and Clinical Medicine
Erlandsson, Malin, 1972 (author)
Gothenburg University,Göteborgs universitet,Institutionen för medicin, avdelningen för reumatologi och inflammationsforskning,Institute of Medicine, Department of Rheumatology and Inflammation Research
Karlsson, Christin, 1956 (author)
Gothenburg University,Göteborgs universitet,Sahlgrenska Cancer Center,Institutionen för medicin, avdelningen för molekylär och klinisk medicin,Institute of Medicine, Department of Molecular and Clinical Medicine
Xu, X. F. (author)
Karolinska Institutet
Brisslert, Mikael, 1974 (author)
Gothenburg University,Göteborgs universitet,Institutionen för medicin, avdelningen för reumatologi och inflammationsforskning,Institute of Medicine, Department of Rheumatology and Inflammation Research
Brakebusch, C. (author)
Wang, D. (author)
Bokarewa, Maria, 1963 (author)
Gothenburg University,Göteborgs universitet,Institutionen för medicin, avdelningen för reumatologi och inflammationsforskning,Institute of Medicine, Department of Rheumatology and Inflammation Research
Sayin, Volkan I., 1983 (author)
Gothenburg University,Göteborgs universitet,Wallenberg Centre for Molecular and Translational Medicine,Institutionen för kliniska vetenskaper, Avdelningen för kirurgi,Sahlgrenska Cancer Center,Institute of Clinical Sciences, Department of Surgery
Bergö, Martin O., 1970 (author)
Karolinska Institutet,Gothenburg University,Göteborgs universitet,Institutionen för medicin, avdelningen för molekylär och klinisk medicin,Sahlgrenska Cancer Center,Institute of Medicine, Department of Molecular and Clinical Medicine
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 (creator_code:org_t)
2019-09-04
2019
English.
In: Nature Communications. - : Springer Science and Business Media LLC. - 2041-1723. ; 10:1
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  • Journal article (peer-reviewed)
Abstract Subject headings
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  • Rho family proteins are prenylated by geranylgeranyltransferase type I (GGTase-I), which normally target proteins to membranes for GTP-loading. However, conditional deletion of GGIase-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 lagapl 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.

Subject headings

MEDICIN OCH HÄLSOVETENSKAP  -- Medicinska och farmaceutiska grundvetenskaper -- Cell- och molekylärbiologi (hsv//swe)
MEDICAL AND HEALTH SCIENCES  -- Basic Medicine -- Cell and Molecular Biology (hsv//eng)

Keyword

central-nervous-system
rho-gtpases
progenitor
statins
cdc42
identification
secretion
promotes
disease
binding
Science & Technology - Other Topics

Publication and Content Type

ref (subject category)
art (subject category)

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