Abstract
RhoA is a ubiquitously expressed cytoplasmic protein that belongs to the family of small GTPases. RhoA acts as a molecular switch that is activated in response to binding of chemokines, cytokines, and growth factors, and via mDia and the ROCK signaling cascade regulates the activation of cytoskeletal proteins, and other factors. This review aims to summarize our current knowledge on the role of RhoA as a general key regulator of immune cell differentiation and function. The contribution of RhoA for the primary functions of innate immune cell types, namely neutrophils, macrophages, and conventional dendritic cells (DC) to (i) get activated by pathogen-derived and endogenous danger signals, (ii) migrate to sites of infection and inflammation, and (iii) internalize pathogens has been fairly established. In activated DC, which constitute the most potent antigen-presenting cells of the immune system, RhoA is also important for the presentation of pathogen-derived antigen and the formation of an immunological synapse between DC and antigen-specific T cells as a prerequisite to induce adaptive T cell responses. In T cells and B cells as the effector cells of the adaptive immune system Rho signaling is pivotal for activation and migration. More recently, mutations of Rho and Rho-modulating factors have been identified to predispose for autoimmune diseases and as causative for hematopoietic malignancies.
Highlights
The rat sarcoma (Ras) superfamily of small guanosine triphosphate (GTP) hydrolase enzymes (GTPases) comprises over 100 members, and Rho family proteins constitute one of the five major branches of this superfamily with 25 proteins encoded by 22 genes in humans and mice [1]
RhoA acts as a molecular switch that is activated in response to binding of chemokines, cytokines, and growth factors, and via mDia and the Rho-associated protein kinases (ROCK) signaling cascade regulates the activation of cytoskeletal proteins, and other factors
This review aims to highlight the functional role of the prototypic GTPase RhoA and of components of the RhoA signaling cascade for innate immune cell types of the myeloid hematopoietic lineage that act as “sentinel” cells to detect and directly eliminate pathogens, comprising neutrophils, monocytes/macrophages, and conventional dendritic
Summary
The rat sarcoma (Ras) superfamily of small guanosine triphosphate (GTP) hydrolase enzymes (GTPases) comprises over 100 members, and Rho family proteins constitute one of the five major branches of this superfamily with 25 proteins encoded by 22 genes in humans and mice [1]. C3 botulinum toxin substrate) [4], and Cdc (cell division control protein 42 homolog) [5] which, besides Rif (Rho in filopodia) [6], represent the group of classical Rho GTPases have been studied most intensely All of these have been shown to contribute to immune cell functions, and functional defects of single GTPases, as well as GTPase regulating factors, have been reported to result in serious immune dysfunction [4,7]. Activated immune cells require dynamic reorganization of their actin cytoskeleton to exert their functions, like phagocytosis of pathogens, migration, and cell-cell interaction [8] All of these processes are regulated, in large part, by small GTPases [9]. The involvement of RhoA proteins in the functions of adaptive immune cells, namely pathogen-specific T cells and B cells, that are recruited to convey an adaptive pathogen-specific immune response are highlighted
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