About this Research Topic
Prenylation consists of the prenyltransferase-catalyzed attachment of hydrophobic isoprenoids to the C-terminal CAAX motif of target proteins, resulting in altered physicochemical properties and increased lipophilicity of those proteins, which enables protein-protein interactions and attachment to the plasma membrane.
Among prenylated proteins, small GTPases belonging to the Ras superfamily represent key proteins in immunology. Small GTPases act as molecular switches participating in the activation of a plethora of signaling pathways, as well as cellular and biological processes. The immunomodulatory effect of prenylation inhibitors and the involvement of K-Ras in cancer development suggested a critical role of prenylation for the immune system. The mevalonate pathway, which is responsible for the synthesis of both cholesterol and isoprenoids, has attracted the attention of the immunology community in the last years. Interestingly, several studies demonstrate that modulation of the mevalonate pathway does not only lead to cholesterol alterations but may also be linked to prenylation-dependent immunomodulation. Recent studies taking advantage of genetically-modified mice and patient samples demonstrated that prenyltransferase activity and, in turn, targeted prenylated proteins, play fundamental role in inflammation in several organs. For instance, GGTase-mediated prenylation control intestinal epithelial integrity, as well as T-cell trafficking, in the context of chronic intestinal inflammation in Inflammatory Bowel Disease.
There is evidence that the function of prenylated proteins appears as crucial players for the operation of the immune system. Thus, regulation of prenyltransferase activity and the mevalonate pathway emerge as key biological processes to be further characterized and exploited in the context of immunomodulation and inflammation. However, several aspects represent limitations to gain further knowledge in this context, such as technical limitations for detection and quantification of prenylated proteins. Furthermore, it is important to consider the overlapping functions between different members of the Ras family, as well as their specific function in diverse cell subtypes and in complex in vivo systems. In the context of regulation of prenylation, little is known about mechanisms controlling the enzymatic activity of prenyltransferases. On the other and, the controversy about the effect of blocking the mevalonate pathway might be due to the lack of distinction between different substances interfering with the pathway at different levels (statins, Nitrogen-containing bisphosphonates or FTIs/GGTIs), and neglecting the role of the different lipid metabolites involved. Recent and future basic studies taking advantage of cell-specific genetically modified experimental models might set light in this context.
The scope of this Research Topic is to gather recent advances about prenlyation and its regulation, as well as the application of the recent knowledge in future therapy strategies in the context of immunomodulation. We welcome Original Research, Review, Mini Review and Methods article types that cover, but are not limited to, the following subtopics:
· Description of the role of prenylation and prenylated proteins in the immune system
· Innovative methods to quantify prenylation, and detect prenylation of single proteins particularly in the immune system
· Mevalonate pathway in immune and other related cells, and drugs interfering with this pathway
· Mechanisms responsible for the regulation of prenylation in the context of immune homeostasis and inflammation
· Immunomodulatory strategies based on prenylation/prenylated proteins
Keywords: Prenylation, Prenyltransferase, Inflammation, Immunomodulation
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