Protein prenylation restrains innate immunity by inhibiting Rac1 effector interactions

Murali K Akula; Mohamed X Ibrahim; Emil G Ivarsson; Omar M Khan; Israiel T Kumar; Malin Erlandsson; Christin Karlsson; Xiufeng Xu; Mikael Brisslert; Cord Brakebusch; Donghai Wang; Maria Bokarewa; Volkan I Sayin; Martin O Bergo

doi:10.1038/s41467-019-11606-x

Protein prenylation restrains innate immunity by inhibiting Rac1 effector interactions

Murali K Akula, Mohamed X Ibrahim, Emil G Ivarsson, Omar M Khan, Israiel T Kumar, Malin Erlandsson, Christin Karlsson, Xiufeng Xu, Mikael Brisslert, Cord Brakebusch, Donghai Wang, Maria Bokarewa, Volkan I Sayin, Martin O Bergo^*

^*Corresponding author for this work

16 Citations (Scopus)

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Abstract

Rho family proteins are prenylated by geranylgeranyltransferase type I (GGTase-I), which normally target proteins to membranes for GTP-loading. However, conditional deletion of GGTase-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 Iqgap1 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.

Original language	English
Article number	3975
Journal	Nature Communications
Volume	10
Issue number	1
Pages (from-to)	1-13
Number of pages	13
ISSN	2041-1723
DOIs	https://doi.org/10.1038/s41467-019-11606-x
Publication status	Published - 1 Dec 2019

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Akula, M. K., Ibrahim, M. X., Ivarsson, E. G., Khan, O. M., Kumar, I. T., Erlandsson, M., Karlsson, C., Xu, X., Brisslert, M., Brakebusch, C., Wang, D., Bokarewa, M., Sayin, V. I., & Bergo, M. O. (2019). Protein prenylation restrains innate immunity by inhibiting Rac1 effector interactions. Nature Communications, 10(1), 1-13. [3975]. https://doi.org/10.1038/s41467-019-11606-x

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title = "Protein prenylation restrains innate immunity by inhibiting Rac1 effector interactions",

abstract = "Rho family proteins are prenylated by geranylgeranyltransferase type I (GGTase-I), which normally target proteins to membranes for GTP-loading. However, conditional deletion of GGTase-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 Iqgap1 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.",

author = "Akula, {Murali K} and Ibrahim, {Mohamed X} and Ivarsson, {Emil G} and Khan, {Omar M} and Kumar, {Israiel T} and Malin Erlandsson and Christin Karlsson and Xiufeng Xu and Mikael Brisslert and Cord Brakebusch and Donghai Wang and Maria Bokarewa and Sayin, {Volkan I} and Bergo, {Martin O}",

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doi = "10.1038/s41467-019-11606-x",

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T1 - Protein prenylation restrains innate immunity by inhibiting Rac1 effector interactions

AU - Akula, Murali K

AU - Ibrahim, Mohamed X

AU - Ivarsson, Emil G

AU - Khan, Omar M

AU - Kumar, Israiel T

AU - Erlandsson, Malin

AU - Karlsson, Christin

AU - Xu, Xiufeng

AU - Brisslert, Mikael

AU - Brakebusch, Cord

AU - Wang, Donghai

AU - Bokarewa, Maria

AU - Sayin, Volkan I

AU - Bergo, Martin O

PY - 2019/12/1

Y1 - 2019/12/1

N2 - Rho family proteins are prenylated by geranylgeranyltransferase type I (GGTase-I), which normally target proteins to membranes for GTP-loading. However, conditional deletion of GGTase-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 Iqgap1 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.

AB - Rho family proteins are prenylated by geranylgeranyltransferase type I (GGTase-I), which normally target proteins to membranes for GTP-loading. However, conditional deletion of GGTase-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 Iqgap1 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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DO - 10.1038/s41467-019-11606-x

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C2 - 31484924

SN - 2041-1723

VL - 10

SP - 1

EP - 13

JO - Nature Communications

JF - Nature Communications

IS - 1

M1 - 3975

ER -

Protein prenylation restrains innate immunity by inhibiting Rac1 effector interactions

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