The perplexing case of the geranylgeranyl transferase–deficient mouse
Mark R. Philips
Mark R. Philips
Published January 25, 2011
Citation Information: J Clin Invest. 2011;121(2):510-513. https://doi.org/10.1172/JCI45952.
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Commentary

The perplexing case of the geranylgeranyl transferase–deficient mouse

Abstract

Proteins that end with a CAAX sequence are targeted to cellular membranes by a series of posttranslational modifications that include prenylation, proteolysis, and carboxyl methylation. Two prenyltransferases modify CAAX proteins: farnesyltransferase and geranylgeranyltransferase type I (GGTase-I). Rho family GTPases that control the actin cytoskeleton and are therefore critical to inflammatory cell function are substrates for GGTase-I. In this issue of the JCI, Khan et al. examined mice in which GGTase-I was conditionally deleted in macrophages. Rather than obtunded cells, the authors found activated Rho proteins in fully functional macrophages that hypersecreted inflammatory cytokines and induced an erosive, inflammatory arthritis. This surprising result calls into question the role of protein geranylgeranylation in inflammatory cell signaling.

Authors

Mark R. Philips

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Figure 1

Regulation of geranylgeranylated Rho GTPases.

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Regulation of geranylgeranylated Rho GTPases. Inactive Rho proteins are ...
Inactive Rho proteins are GDP bound and sequestered in the cytosol by binding to their chaperone RhoGDI, which shields the geranylgeranyl group from the aqueous environment. The activation cycle begins when Rho proteins translocate using their geranylgeranyl lipid moieties to cellular membranes, where they encounter GEFs that catalyze GTP/GDP exchange. GTP-bound Rho proteins engage effectors and are acted on by GAPs that facilitate GTP hydrolysis, returning the Rho proteins to their inactive state that can be extracted from the membrane by free RhoGDI. Central to each step of regulation is the geranylgeranyl lipid. However, in light of the findings of Khan et al., who show that macrophages can function without geranylgeranylation of Rho proteins (3), the role of the lipid modification may have to be reconsidered.