Summary of:
Burgh, Pervolaraki, Turkenburg, Waterham, Frenkel, & Boes. Unprenylated RhoA Contributes to IL-1b Hypersecretion in Mevalonate Kinase Deficiency Model through Stimulation of Rac1 Activity. The Journal of Biological Chemistry Vol. 289, No. 40, pp. 27757-27765, October 2014.
Hereditary autoinflammatory disorders are caused by genetic mutations in molecules involved in regulating the innate immune response. They are characterized by recurrent and usually short attacks of joint pain, rashes, abdominal pain, and fever. One category of these diseases includes hyperimmunoglobulinemia D and periodic fever syndrome (HIDS) and mevalonic aciduria (MA) and is caused by mutations in mevalonate kinase, an enzyme that acts upstream in the mevalonate pathway (Figure 1). Mevalonate kinase is responsible for the production of both non-sterol (farnesylpyrophosphate (FPP) and geranylgeranylpyrophosphate (GGPP) and sterol isoprenoids (cholesterol). Taken together, these disorders are referred to as mevalonate kinase deficiency (MKD). Patients with MKD suffer from periodic fever episodes, which have been attributed, at least in part, to depletion GGPP and subsequent uncontrolled release of the cytokine interleukin (IL)-1b from monocytes and macrophages.
How does GGPP control IL-1b release? GGPP is a lipid moiety that is responsible for the prenylation of proteins including the Rho and Rab families of small GTPases, which cycle between a GTP bound active state and a GDP bound inactive state. Modification of these proteins by GGPP is involved in subcellular localization (membrane attachment) and the control of GTP hydrolysis via interaction with guanine nucleotide exchange factors (GEFs), GTPase activating proteins (GAPs), and GDP dissociation inhibitors (GDIs). GEFs facilitate the exchange of GDP for GTP to generate the activated form. GAPs increase the GTPase activity thereby causing inactivation. Finally, GDIs interact with the prenylated, GDP bound form to inhibit GEF/GAP binding and membrane localization (Figure 2). Lack of prenylation by GGPP has the potential to either activate (for example by blocking GDI interaction) or inhibit (for example by disrupting proper localization) GTPases depending on the circumstances.
In MKD cell culture models, Rac1, a member of the Rho family of GTPases, is known to have reduced prenylation by GGPP leading to increased activity, which has previously been reported to mediate IL-1b hypersecretion. However, activation of Rac1 does not account for all MKD related phenotypes and the exact mechanism of RacI activation has not been determined. This article explores the role of protein prenylation in the function of another Rho family member, RhoA, and hypothesizes that lack of RhoA prenylation contributes to some MKD phenotypes. In order to test this hypothesis, a cell culture model of MKD was used where THP-1 human moncytic cells were treated with simvastatin, a drug that inhibits the enzyme directly upstream of mevalonate kinase, HMG-CoA reductase. As previously observed, simvastatin treatment resulted in increased GTP bound Rac1, indicative of activation. However, simvastatin treatment resulted in decreased GTP-RhoA, indicative of decreased activation. In addition, inhibition of RhoA with C3 transferase (an inhibitor more specific for RhoA than simvastatin) resulted in increased GTP-bound (and therefore activated) Rac1 and IL-1b release. Taken together, these results indicate that decreased prenylation of RhoA leads to inactivation, which subsequently leads to increased Rac1 activation and IL-1b release. Ultimately, this study increased our understanding of molecular mechanisms related to MKD pathogenesis by adding another piece to the puzzle related to IL-1b hypersecretion therefore uncovering a novel target for treatment.
I am especially interested in how GGPP is responsible for the prenylation of Rho and Rab GTPases, since these GTP binding proteins control the cell transduction of proteins and intracellular trafficking, respectively. Furthermore, when there is a lack of prenylation by GGPP these activities can be either inhibited or activated further. This paradigm is somewhat confusing to me and I would love to learn more about the different scenarios that cause either this inhibition or activation.
Like Alissa, I would like to better understand how different situations cause opposite effects when GGPP is not prenylated. I am also interested in understanding more about how RhoA interacts with Rac1 in an inhibitory way. This appears to be a natural control mechanism in the cells, which the researchers have blocked with drugs. What are the endogenous mechanisms for decreasing the prenylation of and, therefore, inactivating RhoA in order to increase the activation of Rac1?
In the first subsection of the Results (Prenylation-deficient RhoA Has Reduced GTP Binding Activity in THP-1 Cells), the authors mention that following treatment of THP-1 cells with simvastatin, increased Rac1 and reduction of RhoA result. However, they continue on to discuss a study by Henneman et al in which MKD cells were treated with the same drug but opposite results were obtained. Does this have an effect on the validity of this particular finding? It seems as though including a study producing opposite effects would challenge their results.
At the beginning of the discussion section of the article, the authors mention that the effects of a lack of prenylation on small GTPases are difficult to determine because of the differences between cell types, the large number of small GTPases, and the large number of feedback pathways. While this article focuses on monocytic cells because they are the main affected cell type in MKD, are there other types of cells that play a role in the disease? If so, do they play a more accessory role or are they also necessary to the development of MKD?
In this article, the authors speculated that with insufficient prenylation, RhoA influences mitochondrial morphology since GTPases regulate mitochondrial fusion of small vesicles into tubular structures. So, they stained THP-1 cells with mitotracker green and red, analyzed via live cell microscopy, and identified cells expressing elongated mitochondria. Like simvastatin treatment, they found that inactivated RhoA induced more cells with elongated mitochondria. However, only simvastatin-treated cells showed increased mitochondrial potential. The authors suggested that during RhoA inactivation additional signals may be required for mitochondrial potential. Moreover, they proposed that either RhoA inactivation (as well as Rho B and C) are not essential in this process or the mitochondrial elongation is a consequence. Regardless, I have learned many times that structure dictates function, and thus am surprised to hear that RhoA may regulate mitochondrial morphology, but not function.
GGPP controls the release of certain cytokines and is involved in the prenylation of proteins in the Rho and Rab families. I am more interested in the circumstances and the mechanisms involved in the lack of prenylation by GGPP. In particular, what specific mechanism of action allows for the activation or the inhibition of the GTPases? What cellular variances allow for these different mechanisms? However, I am also interested in the other causes for MKD related phenotypes since the activation of Rac1 does not account for all phenotypes.
One thing that confused me in this article was the conclusion that mitochondrial elongation is the result of RhoA inactivation. The authors reached this conclusion by treating with either simvastatin or C3 transferase. They propose that as RhoA is the only protein known to be affected by both of these treatments, and RhoB/C have not been reported to affect mitochondria, RhoA is the protein that influences the mitochondria. While there may be a correlation between RhoA and the mitochondrial morphology, I do not think that this shows causation. Intermolecular pathways are so complex that there may be crosstalk between affected proteins, and there may be unknown proteins affected by the treatments. With that being said, I think that the connection between RhoA inactivation and decreased Il-1β is compelling, and deserves further study.
In the first subtopic of the results, “Prenylation-deficient RhoA Has Reduced GTP Binding Activity in THP-1 Cells” one minor thing in particular stood out to me. The authors just described that with simvastatin treatment using a culture-based MKD model with treated THP-1 monocytic cells the quantified amounts of Rac1 and RhoA protein increased and significantly decreased, respectively. They went on to note an opposite effect seen by another lab group (Henneman, et al.). However, they stated that this discrepancy in results could be simply from the use of different cell types. If it is merely a cell type difference I would be interested in comparing and contrasting the two cascades involved. I am not sure what information about these pathways are already known but if there was some distinct factor(s) between the two that could help explain the opposite results that factor could become the focus of a future study and possibly shed some light on many of the unknowns.
When considering the use of simvastatin on cells I found some of the results of this paper to be interesting in regard to Rac1 and RhoA levels. While this paper found Rac1 activity to increase when treated with simvastatin and RhoA activity to decrease, this was not true in another study. When treating fibroblasts, the complete opposite activity was observed in Rac1 and RhoA. I’m specifically interested in seeing research such as this move into clinical treatments and therefore wonder if these different effects could cause future complications while using this drug to treat MKD.
It was interesting that inhibiting RhoA (GGTI-298) by itself was sufficient to increase the amount of fold GTP-bound Rac1 in THP-1 cells. It was also interesting how IL-1B was the only interleukin that showed the difference between RhoA inhibitor and treated with Simvastatin. Moreover, a few research articles talked about induced NF-kB activation, but this article came up with different result. I was confused how RhoA prenylation could affect the mitochondrial trans-membrane potential, but now, I get sense of it! I would love to learn more about other Rho proteins, not only RhoA, could possibly affect the elongation of mitochondria.
I found the connection between RhoA inhibition and IL-1B secretion to be particularly interesting. It is mentioned that this secretion from the inflammasome requires two signals, one to activates the complex and one to form the components. In MKD and simulated MKD by the use of statins reduces prenylation, and pushes the secretion of IL-1B forward. It would be interesting to understand this process in more detail, especially in the context of our lab experiment.
Though one of the main conclusions of the article was related to how Rho A is effected by loss of prenylation in THP-1 monocytic cells, it would be interesting to investigate which protein or signal is responsible for the reduction of IL-1B in the Mevalonate pathway. It was also very interesting to see how a protein such as RhoA can play many roles in different cellular systems. Though this protein is diverse in its function, its diversity is apparently what makes it so difficult to understand when it comes to MKD.
I am particularly interested in the relationship between RhoA and Rac1. The two small Rho GTPases seem to work counter to one another. RhoA inactivation leads to Rac1 activation and increased IL-1β expression. This concept seems counterintuitive as it would seem logical that members of the Rho family would carry out the same role in the cell. I am curious if the activation of members of the Rho family is cytokine specific. Perhaps other cytokines respond differently than IL-1β with Rac1 activity stimulation.
When researchers are using cell models with treatments such as Simvastatin and C3 transferase, how can they assume that previous research is accurate in the mechanistic effect? For example, they confirm the concluded mechanism following the results found with the simvastatin treatment by using a “more specific inhibitor of RhoA”, C3 transferase. How do they know that these drugs are not simultaneously inhibiting or activating another piece to the puzzle that then increases or decreases the activation of RhoA and Rac1 accordingly. I am also curious as to how understanding the portion of the puzzle about hyper-secretion of IL-1B will help with finding a treatment option… Does “treatment” mean more like continuos regulation of symptoms to prolong life rather than cure?
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