Protein prenylation restrains innate immunity by inhibiting Rac1 effector interactions.

Published online

Journal Article

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.

Full Text

Duke Authors

Cited Authors

  • Akula, MK; Ibrahim, MX; Ivarsson, EG; Khan, OM; Kumar, IT; Erlandsson, M; Karlsson, C; Xu, X; Brisslert, M; Brakebusch, C; Wang, D; Bokarewa, M; Sayin, VI; Bergo, MO

Published Date

  • September 4, 2019

Published In

Volume / Issue

  • 10 / 1

Start / End Page

  • 3975 -

PubMed ID

  • 31484924

Pubmed Central ID

  • 31484924

Electronic International Standard Serial Number (EISSN)

  • 2041-1723

Digital Object Identifier (DOI)

  • 10.1038/s41467-019-11606-x

Language

  • eng

Conference Location

  • England