Small Rho GTPases and their associated RhoGEFs mutations promote immunological defects in Primary Immunodeficiencies

2021 ◽  
pp. 106034
Author(s):  
Ana Masara Ahmad Mokhtar ◽  
Ilie Fadzilah binti Hashim
Keyword(s):  
Rho Gtpases ◽  
Primary Immunodeficiencies ◽  
Small Rho Gtpases

scholarly journals Cortical Interneuron Development: a role for small Rho GTPases

2021 ◽  
Author(s):  
Zouzana Kounoupa ◽  
Domna Karagogeos
Keyword(s):  
Cell Cycle ◽  
Rho Gtpases ◽  
Double Mutant ◽  
Epileptic Seizures ◽  
Transgenic Animals ◽  
Postnatal Period ◽  
Cell Therapies ◽  
Cortical Interneurons ◽  
Small Rho Gtpases ◽  
And Migration

GABAergic interneurons control cortical excitation/inhibition balance and are implicated in severe neurodevelopmental disorders. In contrast to the multiplicity of signals underlying the generation and migration of cortical interneurons, the intracellular proteins mediating the response to these cues are mostly unknown. We have demonstrated the unique and diverse roles of the Rho GTPases Rac1 and 3 in cell cycle and morphology in transgenic animals where Rac1 and Rac1/3 were ablated specifically in cortical interneurons. In the Rac1 mutant, progenitors delay their cell cycle exit probably due to a prolonged G1 phase resulting in a cortex with 50% reductions in interneurons and an imbalance of excitation/inhibition in cortical circuits. This disruption in GABAergic inhibition alters glutamatergic function in the adult cortex that could be reversed by enhancement of GABAergic function during an early postnatal period. Furthermore, this disruption disturbs the neuronal synchronization in the adult cortex. In the double mutant, additional severe cytoskeletal defects result in an 80% interneuron decrease. Both lines die from epileptic seizures postnatally. We have made progress towards characterizing the cell cycle defect in Rac1 mutant interneuron progenitors, determining the morphological and synaptic characteristics of single and double mutant interneurons and identifying some of the molecular players by which Racs exert their actions by proteomic analysis. In our present work, we review these studies and discuss open questions and future perspectives. We expect that our data will contribute to the understanding of the function of cortical interneurons, especially since preclinical models of interneuron-based cell therapies are being established.

Small Rho GTPases in the control of cell shape and mobility

2013 ◽  
Vol 71 (9) ◽  
pp. 1703-1721 ◽  
Author(s):  
Arun Murali ◽  
Krishnaraj Rajalingam
Keyword(s):  
Rho Gtpases ◽  
Cell Shape ◽  
Small Rho Gtpases

scholarly journals CB-15 * NKCC1 REGULATES MIGRATION CAPACITY OF GLIOBLASTOMA TUMOR INITIATING CELLS BY MODULATING ACTIN CYTOSKELETON THROUGH SMALL RHO GTPASES

2014 ◽  
Vol 16 (suppl 5) ◽  
pp. v43-v44 ◽  
Author(s):  
P. Schiapparelli ◽  
R. Magana-Maldonado ◽  
S. Hamilla ◽  
L. Sibener ◽  
J. C. Martinez-Gutierrez ◽  
...  
Keyword(s):  
Actin Cytoskeleton ◽  
Rho Gtpases ◽  
Tumor Initiating Cells ◽  
Small Rho Gtpases ◽  
Migration Capacity

scholarly journals Small Rho GTPases and Cholesterol Biosynthetic Pathway Intermediates in African Swine Fever Virus Infection

2011 ◽  
Vol 86 (3) ◽  
pp. 1758-1767 ◽  
Author(s):  
J. I. Quetglas ◽  
B. Hernaez ◽  
I. Galindo ◽  
R. Munoz-Moreno ◽  
M. A. Cuesta-Geijo ◽  
...  
Keyword(s):  
Virus Infection ◽  
Rho Gtpases ◽  
Biosynthetic Pathway ◽  
African Swine Fever Virus ◽  
African Swine Fever ◽  
Fever Virus ◽  
Small Rho Gtpases ◽  
Cholesterol Biosynthetic Pathway

scholarly journals The enteropathogenic Escherichia coli effector NleH inhibits apoptosis induced by Clostridium difficile toxin B

Microbiology ◽  
2010 ◽  
Vol 156 (6) ◽  
pp. 1815-1823 ◽  
Author(s):  
Keith S. Robinson ◽  
Aurelie Mousnier ◽  
Cordula Hemrajani ◽  
Neil Fairweather ◽  
Cedric N. Berger ◽  
...  
Keyword(s):  
Escherichia Coli ◽  
Clostridium Difficile ◽  
Rho Gtpases ◽  
Nucleotide Exchange ◽  
Nuclear Condensation ◽  
Apoptotic Pathway ◽  
Small Rho Gtpases ◽  
Clostridium Difficile Toxin B ◽  
Apoptotic Activity ◽  
Induced Apoptosis

Clostridium difficile is a leading cause of nosocomial infections, causing a spectrum of diseases ranging from diarrhoea to pseudomembranous colitis triggered by a range of virulence factors including C. difficile toxins A (TcdA) and B (TcdB). TcdA and TcdB are monoglucosyltransferases that irreversibly glycosylate small Rho GTPases, inhibiting their ability to interact with their effectors, guanine nucleotide exchange factors, and membrane partners, leading to disruption of downstream signalling pathways and cell death. In addition, TcdB targets the mitochondria, inducing the intrinsic apoptotic pathway resulting in TcdB-mediated apoptosis. Modulation of apoptosis is a common strategy used by infectious agents. Recently, we have shown that the enteropathogenic Escherichia coli (EPEC) type III secretion system effector NleH has a broad-range anti-apoptotic activity. In this study we examined the effects of NleH on cells challenged with TcdB. During infection with wild-type EPEC, NleH inhibited TcdB-induced apoptosis at both low and high toxin concentrations. Transfected nleH1 alone was sufficient to block TcdB-induced cell rounding, nuclear condensation, mitochondrial swelling and lysis, and activation of caspase-3. These results show that NleH acts via a global anti-apoptotic pathway.

scholarly journals ERM Proteins at the Crossroad of Leukocyte Polarization, Migration and Intercellular Adhesion

2020 ◽  
Vol 21 (4) ◽  
pp. 1502 ◽  
Author(s):  
Almudena García-Ortiz ◽  
Juan Manuel Serrador
Keyword(s):  
Rho Gtpases ◽  
Transmembrane Proteins ◽  
Cellular Structures ◽  
Ferm Domain ◽  
Erm Proteins ◽  
Immune Synapse ◽  
Small Rho Gtpases ◽  
And Migration ◽  
Wide Assortment ◽  
Effector Immune Response

Ezrin, radixin and moesin proteins (ERMs) are plasma membrane (PM) organizers that link the actin cytoskeleton to the cytoplasmic tail of transmembrane proteins, many of which are adhesion receptors, in order to regulate the formation of F-actin-based structures (e.g., microspikes and microvilli). ERMs also effect transmission of signals from the PM into the cell, an action mainly exerted through the compartmentalized activation of the small Rho GTPases Rho, Rac and Cdc42. Ezrin and moesin are the ERMs more highly expressed in leukocytes, and although they do not always share functions, both are mainly regulated through phosphatidylinositol 4,5-bisphosphate (PIP2) binding to the N-terminal band 4.1 protein-ERM (FERM) domain and phosphorylation of a conserved Thr in the C-terminal ERM association domain (C-ERMAD), exerting their functions through a wide assortment of mechanisms. In this review we will discuss some of these mechanisms, focusing on how they regulate polarization and migration in leukocytes, and formation of actin-based cellular structures like the phagocytic cup-endosome and the immune synapse in macrophages/neutrophils and lymphocytes, respectively, which represent essential aspects of the effector immune response.

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