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 and Martin O. Bergo ()
Additional contact information
Murali K. Akula: University of Gothenburg
Mohamed X. Ibrahim: University of Gothenburg
Emil G. Ivarsson: University of Gothenburg
Omar M. Khan: Francis Crick Research Institute
Israiel T. Kumar: University of Gothenburg
Malin Erlandsson: University of Gothenburg
Christin Karlsson: University of Gothenburg
Xiufeng Xu: Karolinska Institutet
Mikael Brisslert: University of Gothenburg
Cord Brakebusch: University of Copenhagen
Donghai Wang: Duke University School of Medicine
Maria Bokarewa: University of Gothenburg
Volkan I. Sayin: University of Gothenburg
Martin O. Bergo: University of Gothenburg

Nature Communications, 2019, vol. 10, issue 1, 1-13

Abstract: 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.

Date: 2019
References: Add references at CitEc
Citations:

Downloads: (external link)
https://www.nature.com/articles/s41467-019-11606-x Abstract (text/html)

Related works:
This item may be available elsewhere in EconPapers: Search for items with the same title.

Export reference: BibTeX RIS (EndNote, ProCite, RefMan) HTML/Text

Persistent link: https://EconPapers.repec.org/RePEc:nat:natcom:v:10:y:2019:i:1:d:10.1038_s41467-019-11606-x

Ordering information: This journal article can be ordered from
https://www.nature.com/ncomms/

DOI: 10.1038/s41467-019-11606-x

Access Statistics for this article

Nature Communications is currently edited by Nathalie Le Bot, Enda Bergin and Fiona Gillespie

More articles in Nature Communications from Nature
Bibliographic data for series maintained by Sonal Shukla () and Springer Nature Abstracting and Indexing ().