ARHGAP25, a novel Rac GTPase-activating protein, regulates phagocytosis in human neutrophilic granulocytes

Csépányi-Kömi, Roland; Sirokmány, Gábor; Geiszt, Miklós; Ligeti, Erzsébet

doi:10.1182/blood-2010-12-324053

Cited by 54 publications

(91 citation statements)

References 41 publications

(50 reference statements)

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“…GSTtagged full length ARHGAP25 was produced as previously decribed in ref. [44]. The GAP domain of ARHGAP35 (residues 1191-1499) was produced in the form of GST fusion protein and purified as described in [45].…”

Section: Methodsmentioning

confidence: 99%

“…Antibodies against ARHGAP1 and ARHGAP25 were raised in rabbits and characterized as described in ref. [40,44]. Isotype control polyclonal rabbit-Ab [γ-32 P]GTP was from Izotóp Intézet, Hungary.…”

Section: Methodsmentioning

confidence: 99%

“…Immunoblots revealed the presence of all identified RacGAPs both in the cytosolic and in the membrane fractions [40,44]. To mimic the potential effect of cytosolic RacGAPs, we first added these proteins to the semirecombinant cell-free O2 •--generation system.…”

Section: Effect Of Added Racgaps On Nox2 Activitymentioning

confidence: 99%

“…Interestingly, ARHGAP1, that was expressed to a similar extent and had similar RacGAP activity as ARHGAP25, did not affect phagocytosis [44]. These data raised the question of specificity of different RacGAPs in the regulation of the phagocytic NADPH oxidase.…”

Section: Introductionmentioning

confidence: 96%

“…Recently, ARHGAP25 has been cloned and shown to be a RacGAP preferentially expressed in hemopoetic cells. In neutrophilic granulocytes it functions as a negative regulator of phagocytosis [44].…”

Section: Introductionmentioning

confidence: 99%

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Role of Rac GTPase activating proteins in regulation of NADPH oxidase in human neutrophils

Lörincz

Szarvas

Smith

et al. 2014

Free Radical Biology and Medicine

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Precise spatiotemporal regulation of O2 •--generating NADPH oxidases (Nox) is a vital requirement. In the case of Nox1-3, which depend on the small GTPase Rac, acceleration of GTP hydrolysis by GTPase activating protein (GAP) could represent a feasible temporal control mechanism. Our goal was to investigate the molecular interactions between RacGAPs and phagocytic Nox2 in neutrophilic granulocytes. In structural studies we revealed that simultaneous interaction of Rac with its effector protein p67 phox and regulatory protein RacGAP was sterically possible. The effect of RacGAPs was experimentally investigated in a cell-free O2 •--generating system consisting of isolated membranes and recombinant p47 phox and p67 phox proteins. Addition of soluble RacGAPs decreased O2 •--production and there was no difference in the effect of four RacGAPs previously identified in neutrophils. Depletion of membrane-associated RacGAPs had selective effect: a decrease in ARHGAP1 or ARHGAP25 level increased O2 •--production but a depletion of ARHGAP35 had no effect.Only membrane-localized RacGAPs seem to be able to interact with Rac when it is assembled in the Nox2 complex. Thus, in neutrophils multiple RacGAPs are involved in the control of O2 •--production by Nox2, allowing selective regulation via different signaling pathways.

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Section: Methodsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Section: Effect Of Added Racgaps On Nox2 Activitymentioning

confidence: 99%

Section: Introductionmentioning

confidence: 96%

Section: Introductionmentioning

confidence: 99%

See 3 more Smart Citations

Role of Rac GTPase activating proteins in regulation of NADPH oxidase in human neutrophils

Lörincz

Szarvas

Smith

et al. 2014

Free Radical Biology and Medicine

Self Cite

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Piezoelectric Nanostructured Surface for Ultrasound‐Driven Immunoregulation to Rescue Titanium Implant Infection

Chen

et al. 2023

Adv Funct Materials

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Treating bacterial biofilm infections on implanted materials remains challenging in clinical practice, as bacteria can be resistant by weakening the host defense from immune cells like macrophages. Herein, a metal-piezoelectric hetero-nanostructure with mechanical energy-driven antimicrobial property is in situ constructed on the Ti implant. Under ultrasonic irradiation, the formed piezotronic Ti (piezoTi) can promote the generation of reactive oxygen species (ROS) by facilitating local charge transfer at the surface, thus leading to piezodynamic killing of Staphylococcus aureus (S. aureus) while downregulating biofilm-forming genes. In addition, the stimulated macrophages on piezoTi display potent phagocytosis and anti-bacterial activity through the activation of PI3K-AKT and MAPK pathway. As a demonstration, one-time ultrasound irradiation of piezoTi pillar implanted in an osteomyelitis model efficiently eliminates the S. aureus biofilm infection and rescues the implant with enhanced osteointegration. By the synergistic effect of ultrasound-driven piezodynamic therapy and immuno-regulation, the proposed piezoelectric nanostructured surface can endow Ti implants with highly efficient antibacterial performance in an antibiotic-free, noninvasive, and on-demand manner.

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AnARHGAP25variant links aberrantRac1function to early‐onset skeletal fragility

et al. 2021

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Ras homologous guanosine triphosphatases (RhoGTPases) control several cellular functions, including cytoskeletal actin remodeling and cell migration. Their activities are downregulated by GTPase-activating proteins (GAPs). Although RhoGTPases are implicated in bone remodeling and osteoclast and osteoblast function, their significance in human bone health and disease remains elusive. Here, we report defective RhoGTPase regulation as a cause of severe, early-onset, autosomal-dominant skeletal fragility in a threegeneration Finnish family. Affected individuals (n = 13) presented with multiple low-energy peripheral and vertebral fractures despite normal bone mineral density (BMD). Bone histomorphometry suggested reduced bone volume, low surface area covered by osteoblasts and osteoclasts, and low bone turnover. Exome sequencing identified a novel heterozygous missense variant c.652G>A (p.G218R) in ARHGAP25, encoding a GAP for Rho-family GTPase Rac1. Variants in the ARHGAP25 5 0 untranslated region (UTR) also associated with BMD and fracture risk in the general population, across multiple genomewide association study (GWAS) meta-analyses (lead variant rs10048745). ARHGAP25 messenger RNA (mRNA) was expressed in macrophage colony-stimulating factor (M-CSF)-stimulated human monocytes and mouse osteoblasts, indicating a possible role for ARHGAP25 in osteoclast and osteoblast differentiation and activity. Studies on subject-derived osteoclasts from peripheral blood mononuclear cells did not reveal robust defects in mature osteoclast formation or resorptive activity. However, analysis of osteosarcoma cells overexpressing the ARHGAP25 G218R-mutant, combined with structural modeling, confirmed that the mutant protein had decreased GAP-activity against Rac1, resulting in elevated Rac1 activity, increased cell spreading, and membrane ruffling. Our findings indicate that mutated ARHGAP25 causes aberrant Rac1 function and consequently abnormal bone metabolism, highlighting the importance of RhoGAP signaling in bone metabolism in familial forms of skeletal fragility and in the general population, and expanding our understanding of the molecular pathways underlying skeletal fragility.

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ARHGAP25, a novel Rac GTPase-activating protein, regulates phagocytosis in human neutrophilic granulocytes

Abstract: Members of the

Cited by 54 publications

References 41 publications

Role of Rac GTPase activating proteins in regulation of NADPH oxidase in human neutrophils

Role of Rac GTPase activating proteins in regulation of NADPH oxidase in human neutrophils

Piezoelectric Nanostructured Surface for Ultrasound‐Driven Immunoregulation to Rescue Titanium Implant Infection

AnARHGAP25variant links aberrantRac1function to early‐onset skeletal fragility

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