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Protein prenylation restrains innate immunity by inhibiting Rac1 effector interactions

Journal article
Authors Murali K Akula
Mohamed X Ibrahim
Emil G. Ivarsson
O. M. Khan
Israiel T. Kumar
Malin Erlandsson
Christin Karlsson
X. F. Xu
Mikael Brisslert
C. Brakebusch
D. Wang
Maria Bokarewa
Volkan I. Sayin
Martin O. Bergo
Published in Nature Communications
Volume 10
ISSN 2041-1723
Publication year 2019
Published at Institute of Clinical Sciences, Department of Surgery
Sahlgrenska Cancer Center
Institute of Medicine, Department of Rheumatology and Inflammation Research
Institute of Medicine, Department of Molecular and Clinical Medicine
Language en
Keywords central-nervous-system, rho-gtpases, progenitor, statins, cdc42, identification, secretion, promotes, disease, binding, Science & Technology - Other Topics
Subject categories Cell and Molecular Biology


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.

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