scholarly journals The Cytotoxic Necrotizing Factors (CNFs)—A Family of Rho GTPase-Activating Bacterial Exotoxins

Toxins ◽  
2021 ◽  
Vol 13 (12) ◽  
pp. 901
Author(s):  
Paweena Chaoprasid ◽  
Petra Dersch
Keyword(s):  
Rho Gtpases ◽  
Pathogenic Bacteria ◽  
Immune Cell ◽  
Rho Gtpase ◽  
Current Knowledge ◽  
Single Chain ◽  
Tissue Integrity ◽  
Cell Tissue ◽  
Functional Consequences ◽  
Cell Processes

The cytotoxic necrotizing factors (CNFs) are a family of Rho GTPase-activating single-chain exotoxins that are produced by several Gram-negative pathogenic bacteria. Due to the pleiotropic activities of the targeted Rho GTPases, the CNFs trigger multiple signaling pathways and host cell processes with diverse functional consequences. They influence cytokinesis, tissue integrity, cell barriers, and cell death, as well as the induction of inflammatory and immune cell responses. This has an enormous influence on host–pathogen interactions and the severity of the infection. The present review provides a comprehensive insight into our current knowledge of the modular structure, cell entry mechanisms, and the mode of action of this class of toxins, and describes their influence on the cell, tissue/organ, and systems levels. In addition to their toxic functions, possibilities for their use as drug delivery tool and for therapeutic applications against important illnesses, including nervous system diseases and cancer, have also been identified and are discussed.

scholarly journals Regulation of Rho GTPases in the Vasculature by Cullin3-Based E3 Ligase Complexes

2021 ◽  
Vol 9 ◽  
Author(s):  
Fabienne Podieh ◽  
Peter L. Hordijk
Keyword(s):  
Rho Gtpases ◽  
Vascular Function ◽  
Rho Gtpase ◽  
Current Knowledge ◽  
E3 Ligase ◽  
Small Gtpases ◽  
E3 Ligases ◽  
Cellular Processes ◽  
Ubiquitin E3 Ligase ◽  
Cytoskeletal Dynamics

Cullin3-based ubiquitin E3 ligases induce ubiquitination of substrates leading to their proteasomal or lysosomal degradation. BTB proteins serve as adaptors by binding to Cullin3 and recruiting substrate proteins, which enables specific recognition of a broad spectrum of targets. Hence, Cullin3 and its adaptors are involved in myriad cellular processes and organ functions. Cullin3-based ubiquitin E3 ligase complexes target small GTPases of the Rho subfamily, which are key regulators of cytoskeletal dynamics and cell adhesion. In this mini review, we discuss recent insights in Cullin3-mediated regulation of Rho GTPases and their impact on cellular function and disease. Intriguingly, upstream regulators of Rho GTPases are targeted by Cullin3 complexes as well. Thus, Rho GTPase signaling is regulated by Cullin3 on multiple levels. In addition, we address current knowledge of Cullin3 in regulating vascular function, focusing on its prominent role in endothelial barrier function, angiogenesis and the regulation of blood pressure.

Rho GTPase Activating Protein 9 (ARHGAP9) in Human Cancers

2021 ◽  
Vol 16 ◽  
Author(s):  
Wenping Song ◽  
Jinhua Chen ◽  
Shuolei Li ◽  
Ding Li ◽  
Yongna Zhang ◽  
...  
Keyword(s):  
Cancer Treatment ◽  
Cancer Progression ◽  
Rho Gtpases ◽  
Rho Gtpase ◽  
Current Knowledge ◽  
Clinical Success ◽  
Predictive Biomarker ◽  
Migration And Invasion ◽  
Targeted Drugs ◽  
Gtpase Activating Protein

Background: In recent years, targeted therapy combined with traditional chemoradiotherapy and surgery has brought new opportunities for cancer treatment. However, the complex characteristics of cancer, such as heterogeneity and diversity, limit the clinical success of targeted drugs. The discovery of new cancer targets and deepening the understanding of their functional mechanisms will bring additional promising application prospects for the research and development of personalized cancer-targeted drugs. Objective: This study aimed to summarize the role of the Rho GTPase activating protein 9 (ARHGAP9) gene in tumorigenesis and development to discover therapeutic targets for cancer in the future. Methods: For this review, we collected patents from the databases of Espacenet and WIPO and articles from PubMed that were related to the ARHGAP9 gene. Results: Genetic/epigenetic variations and abnormal expression of the ARHGAP9 gene are closely associated with a variety of diseases, including cancer. ARHGAP9 can inactivate Rho GTPases by hydrolyzing GTP into GDP and regulate cancer cellular events, including proliferation, differentiation, apoptosis, migration and invasion, by inhibiting JNK/ERK/p38 and PI3K/AKT signaling pathways. In addition to reviewing these mechanisms, we assessed various patents on ARHGAP9 to determine whether ARHGAP9 might be used as a predictive biomarker for diagnosis/prognosis evaluation and a druggable target for cancer treatment. Conclusion: In this review, the current knowledge of ARHGAP9 in cancer is summarized with an emphasis on its molecular function, regulatory mechanism and disease implications. Its characterization is crucial to understanding its important roles during different stages of cancer progression and therapy as a predictive biomarker and/or target.

scholarly journals Dysregulation of Rho GTPases in Human Cancers

Cancers ◽  
2020 ◽  
Vol 12 (5) ◽  
pp. 1179 ◽  
Author(s):  
Haiyoung Jung ◽  
Suk Ran Yoon ◽  
Jeewon Lim ◽  
Hee Jun Cho ◽  
Hee Gu Lee
Keyword(s):  
Cancer Progression ◽  
Rho Gtpases ◽  
Cell Cycle Progression ◽  
Rho Gtpase ◽  
Current Knowledge ◽  
New Drugs ◽  
Guanine Nucleotide ◽  
Nucleotide Exchange ◽  
Human Cancers ◽  
Cytoskeletal Dynamics

Rho GTPases play central roles in numerous cellular processes, including cell motility, cell polarity, and cell cycle progression, by regulating actin cytoskeletal dynamics and cell adhesion. Dysregulation of Rho GTPase signaling is observed in a broad range of human cancers, and is associated with cancer development and malignant phenotypes, including metastasis and chemoresistance. Rho GTPase activity is precisely controlled by guanine nucleotide exchange factors, GTPase-activating proteins, and guanine nucleotide dissociation inhibitors. Recent evidence demonstrates that it is also regulated by post-translational modifications, such as phosphorylation, ubiquitination, and sumoylation. Here, we review the current knowledge on the role of Rho GTPases, and the precise mechanisms controlling their activity in the regulation of cancer progression. In addition, we discuss targeting strategies for the development of new drugs to improve cancer therapy.

scholarly journals Functional and Therapeutic Relevance of Rho GTPases in Innate Immune Cell Migration and Function during Inflammation: An In Silico Perspective

2021 ◽  
Vol 2021 ◽  
pp. 1-10
Author(s):  
Pankaj Dipankar ◽  
Puneet Kumar ◽  
Shiba Prasad Dash ◽  
Pranita P. Sarangi
Keyword(s):  
Cell Migration ◽  
Immune Cells ◽  
Rho Gtpases ◽  
Inflammatory Cell ◽  
Immune Cell ◽  
Rho Gtpase ◽  
Innate Immune ◽  
Molecular Organization ◽  
Exchange Reactions ◽  
And Function

Systematic regulation of leukocyte migration to the site of infection is a vital step during immunological responses. Improper migration and localization of immune cells could be associated with disease pathology as seen in systemic inflammation. Rho GTPases act as molecular switches during inflammatory cell migration by cycling between Rho-GDP (inactive) to Rho-GTP (active) forms and play an essential role in the precise regulation of actin cytoskeletal dynamics as well as other immunological functions of leukocytes. Available reports suggest that the dysregulation of Rho GTPase signaling is associated with various inflammatory diseases ranging from mild to life-threatening conditions. Therefore, it is crucial to understand the step-by-step activation and inactivation of GTPases and the functioning of different Guanine Nucleotide Exchange Factors (GEFs) and GTPase-Activating Proteins (GAPs) that regulate the conversion of GDP to GTP and GTP to GDP exchange reactions, respectively. Here, we describe the molecular organization and activation of various domains of crucial elements associated with the activation of Rho GTPases using solved PDB structures. We will also present the latest evidence available on the relevance of Rho GTPases in the migration and function of innate immune cells during inflammation. This knowledge will help scientists design promising drug candidates against the Rho-GTPase-centric regulatory molecules regulating inflammatory cell migration.

scholarly journals Rab35 Mediates Transport of Cdc42 and Rac1 to the Plasma Membrane during Phagocytosis

2010 ◽  
Vol 30 (6) ◽  
pp. 1421-1433 ◽  
Author(s):  
Jaewon Shim ◽  
Sun-Min Lee ◽  
Myeong Sup Lee ◽  
Joonsun Yoon ◽  
Hee-Seok Kweon ◽  
...  
Keyword(s):  
Innate Immunity ◽  
Plasma Membrane ◽  
Rho Gtpases ◽  
Immune Cell ◽  
Rho Gtpase ◽  
Vesicle Transport ◽  
Membrane Protrusion ◽  
Actin Network ◽  
Actin Remodeling ◽  
Accessory Molecules

ABSTRACT Phagocytosis of invading microbes requires dynamic rearrangement of the plasma membrane and its associated cytoskeletal actin network. The polarization of Cdc42 and Rac1 Rho GTPases to the site of plasma membrane protrusion is responsible for the remodeling of actin structures. However, the mechanism of Rho GTPase recruitment to these sites and the identities of accessory molecules involved in this process are not well understood. In this study, we uncovered several new components involved in innate immunity in Drosophila melanogaster. Our data demonstrate that Rab35 is a regulator of vesicle transport required specifically for phagocytosis. Moreover, recruitment of Cdc42 and Rac1 to the sites of filopodium and lamellipodium formation is Rab35 dependent and occurs by way of microtubule tracks. These results implicate Rab35 as the immune cell-specific regulator of vesicle transport within the actin-remodeling complex.

scholarly journals Turning Platelets Off and On: Role of RhoGAPs and RhoGEFs in Platelet Activity

2022 ◽  
Vol 8 ◽  
Author(s):  
Shane P. Comer
Keyword(s):  
Rho Gtpases ◽  
Bound States ◽  
Rho Gtpase ◽  
Current Knowledge ◽  
Thrombus Formation ◽  
Nucleotide Exchange ◽  
Platelet Activity ◽  
Platelet Surface ◽  
Guanine Nucleotide Exchange ◽  
Nucleotide Exchange Factors

Platelet cytoskeletal reorganisation is a critical component of platelet activation and thrombus formation in haemostasis. The Rho GTPases RhoA, Rac1 and Cdc42 are the primary drivers in the dynamic reorganisation process, leading to the development of filopodia and lamellipodia which dramatically increase platelet surface area upon activation. Rho GTPases cycle between their active (GTP-bound) and inactive (GDP-bound) states through tightly regulated processes, central to which are the guanine nucleotide exchange factors (GEFs) and GTPase-activating proteins (GAPs). GEFs catalyse the dissociation of GDP by inducing changes in the nucleotide binding site, facilitating GTP binding and activating Rho GTPases. By contrast, while all GTPases possess intrinsic hydrolysing activity, this reaction is extremely slow. Therefore, GAPs catalyse the hydrolysis of GTP to GDP, reverting Rho GTPases to their inactive state. Our current knowledge of these proteins is constantly being updated but there is considerably less known about the functionality of Rho GTPase specific GAPs and GEFs in platelets. In the present review, we discuss GAP and GEF proteins for Rho GTPases identified in platelets, their regulation, biological function and present a case for their further study in platelets.

scholarly journals Regulation of Rho GTPases by RhoGDIs in Human Cancers

Cells ◽  
2019 ◽  
Vol 8 (9) ◽  
pp. 1037 ◽  
Author(s):  
Cho ◽  
Kim ◽  
Baek ◽  
Kim ◽  
Lee
Keyword(s):  
Cell Migration ◽  
Cancer Progression ◽  
Anticancer Agents ◽  
Rho Gtpases ◽  
Rho Gtpase ◽  
Regulatory Mechanisms ◽  
Malignant Phenotype ◽  
Cellular Processes ◽  
Human Cancers

Rho GDP dissociation inhibitors (RhoGDIs) play important roles in various cellular processes, including cell migration, adhesion, and proliferation, by regulating the functions of the Rho GTPase family. Dissociation of Rho GTPases from RhoGDIs is necessary for their spatiotemporal activation and is dynamically regulated by several mechanisms, such as phosphorylation, sumoylation, and protein interaction. The expression of RhoGDIs has changed in many human cancers and become associated with the malignant phenotype, including migration, invasion, metastasis, and resistance to anticancer agents. Here, we review how RhoGDIs control the function of Rho GTPases by regulating their spatiotemporal activity and describe the regulatory mechanisms of the dissociation of Rho GTPases from RhoGDIs. We also discuss the role of RhoGDIs in cancer progression and their potential uses for therapeutic intervention.

scholarly journals Targeting Haemagglutinin Antigen of Avian Influenza Virus to Chicken Immune Cell Receptors Dec205 and CD11c Induces Differential Immune-Potentiating Responses

Vaccines ◽  
2021 ◽  
Vol 9 (7) ◽  
pp. 784
Author(s):  
Angita Shrestha ◽  
Jean-Remy Sadeyen ◽  
Deimante Lukosaityte ◽  
Pengxiang Chang ◽  
Marielle Van Hulten ◽  
...  
Keyword(s):  
Influenza A ◽  
Immune Cell ◽  
Ex Vivo ◽  
Protective Efficacy ◽  
Haemagglutination Inhibition ◽  
Primary Vaccination ◽  
Antigen Delivery ◽  
Single Chain ◽  
Protective Antigens ◽  
Single Chain Fragment Variable

Improving the immunogenicity and protective efficacy of vaccines is critical to reducing disease impacts. One strategy used to enhance the immunogenicity of vaccines is the selective delivery of protective antigens to the antigen presenting cells (APCs). In this study, we have developed a targeted antigen delivery vaccine (TADV) system by recombinantly fusing the ectodomain of hemagglutinin (HA) antigen of H9N2 influenza A virus to single chain fragment variable (scFv) antibodies specific for the receptors expressed on chicken APCs; Dec205 and CD11c. Vaccination of chickens with TADV containing recombinant H9HA Foldon-Dec205 scFv or H9HA Foldon-CD11c scFv proteins elicited faster (as early as day 6 post primary vaccination) and higher anti-H9HA IgM and IgY, haemagglutination inhibition, and virus neutralisation antibodies compared to the untargeted H9HA protein. Comparatively, CD11c scFv conjugated H9HA protein showed higher immunogenic potency compared to Dec205 scFv conjugated H9HA protein. The higher immune potentiating ability of CD11c scFv was also reflected in ex-vivo chicken splenocyte stimulation assay, whereby H9HA Foldon-CD11c scFv induced higher levels of cytokines (IFNγ, IL6, IL1β, and IL4) compared to H9HA Foldon-Dec205 scFv. Overall, the results conclude that TADV could be a better alternative to the currently available inactivated virus vaccines.

scholarly journals The Multiple Functions of Rho GTPases in Fission Yeasts

Cells ◽  
2021 ◽  
Vol 10 (6) ◽  
pp. 1422
Author(s):  
Jero Vicente-Soler ◽  
Teresa Soto ◽  
Alejandro Franco ◽  
José Cansado ◽  
Marisa Madrid
Keyword(s):  
Fission Yeast ◽  
Rho Gtpases ◽  
Current Knowledge ◽  
Model Organism ◽  
Nucleotide Exchange ◽  
Guanine Nucleotide Exchange ◽  
Nucleotide Exchange Factors ◽  
Physiological Processes ◽  
Evolutionary Changes ◽  
Rho Family

The Rho family of GTPases represents highly conserved molecular switches involved in a plethora of physiological processes. Fission yeast Schizosaccharomyces pombe has become a fundamental model organism to study the functions of Rho GTPases over the past few decades. In recent years, another fission yeast species, Schizosaccharomyces japonicus, has come into focus offering insight into evolutionary changes within the genus. Both fission yeasts contain only six Rho-type GTPases that are spatiotemporally controlled by multiple guanine–nucleotide exchange factors (GEFs) and GTPase-activating proteins (GAPs), and whose intricate regulation in response to external cues is starting to be uncovered. In the present review, we will outline and discuss the current knowledge and recent advances on how the fission yeasts Rho family GTPases regulate essential physiological processes such as morphogenesis and polarity, cellular integrity, cytokinesis and cellular differentiation.

scholarly journals Rho GTPases as Key Molecular Players within Intestinal Mucosa and GI Diseases

Cells ◽  
2021 ◽  
Vol 10 (1) ◽  
pp. 66
Author(s):  
Rashmita Pradhan ◽  
Phuong A. Ngo ◽  
Luz d. C. Martínez-Sánchez ◽  
Markus F. Neurath ◽  
Rocío López-Posadas
Keyword(s):  
Intestinal Mucosa ◽  
Rho Gtpases ◽  
Current Knowledge ◽  
Cell Types ◽  
Effector Proteins ◽  
Special Focus ◽  
Specific Cell ◽  
Rho Proteins

Rho proteins operate as key regulators of the cytoskeleton, cell morphology and trafficking. Acting as molecular switches, the function of Rho GTPases is determined by guanosine triphosphate (GTP)/guanosine diphosphate (GDP) exchange and their lipidation via prenylation, allowing their binding to cellular membranes and the interaction with downstream effector proteins in close proximity to the membrane. A plethora of in vitro studies demonstrate the indispensable function of Rho proteins for cytoskeleton dynamics within different cell types. However, only in the last decades we have got access to genetically modified mouse models to decipher the intricate regulation between members of the Rho family within specific cell types in the complex in vivo situation. Translationally, alterations of the expression and/or function of Rho GTPases have been associated with several pathological conditions, such as inflammation and cancer. In the context of the GI tract, the continuous crosstalk between the host and the intestinal microbiota requires a tight regulation of the complex interaction between cellular components within the intestinal tissue. Recent studies demonstrate that Rho GTPases play important roles for the maintenance of tissue homeostasis in the gut. We will summarize the current knowledge on Rho protein function within individual cell types in the intestinal mucosa in vivo, with special focus on intestinal epithelial cells and T cells.

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