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Hematopoietic-specific Rho GTPases Rac2 and RhoH and human blood disorders
Open accessAbstract
The small guanosine triphosphotases (GTPases) Rho proteins are members of the Ras-like superfamily. Similar to Ras, most Rho GTPases cycle between active GTP-bound, and inactive GDP-bound conformations and act as molecular switches that control multiple cellular functions. While most Rho GTPases are expressed widely, the expression of Rac2 and RhoH are restricted to hematopoietic cells. RhoH is an atypical GTPase that lacks GTPase activity and remains in the active conformation. The generation of mouse knock-out lines has led to new understanding of the functions of both of these proteins in blood cells. The phenotype of these mice also led to the identification of mutations in human RAC2 and RHOH genes and the role of these proteins in immunodeficiency diseases. This review outlines the basic biology of Rho GTPases, focusing on Rac and RhoH and summarizes human diseases associated with mutations of these genes.
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TL;DR
This review summarizes the biology of the hematopoietic-restricted Rho GTPases Rac2 and RhoH and how mouse knockout models predicted human immunodeficiency phenotypes. It describes the dominant-negative RAC2 D57N mutation causing severe phagocytic immunodeficiency and homozygous RHOH truncation causing T cell defects with susceptibility to EV-HPV infections.
Key findings
- Rac2 is hematopoietic-specific and required for neutrophil chemotaxis, superoxide production, and F-actin assembly; Rac2−/− mice show leukocytosis with neutrophilia, defective long-term HSC engraftment, and increased susceptibility to invasive fungal infections.
- A spontaneous dominant-negative D57N RAC2 mutation (G169A) was identified in two patients with severe phagocytic immunodeficiency; both had life-threatening bacterial infections in infancy, leukocytosis with neutrophilia, absent pus at infection sites, and defective fMLP-induced F-actin formation, chemotaxis, and (in patient 1) superoxide production.
- RhoH is an atypical GTPase that is GTPase-deficient and remains constitutively GTP-bound; Rhoh−/− mice show a block in T cell maturation at the DN3 and DP stages, T cell lymphopenia, and impaired Zap70 recruitment to the immunological synapse.
- A homozygous Y38X RHOH mutation was found in two siblings with Epidermodysplasia verruciformis; they lacked naïve T cells and recent thymic emigrants, had reduced β7+ skin-homing T cells, and their immortalized T cells failed to proliferate or phosphorylate Zap70 in response to TCR stimulation.
Methods
- Narrative review; no primary experimental data reported.
- Synthesizes published mouse knockout studies (Rac2−/−, Rac1/Rac2 double knockout, Rhoh−/−) and human genetic findings (RAC2 D57N patients; RHOH Y38X family identified by homozygosity mapping with high-density SNP array and whole-exome sequencing).
- Describes biochemical and cellular assays from cited work, including neutrophil chemotaxis, F-actin assembly, NADPH oxidase/superoxide production, TCR-stimulated proliferation, and Zap70 phosphorylation.
Limitations
- As a review, it presents no new primary data; all findings are drawn from cited studies.
- The authors state the relatively mild human phenotype of RHOH deficiency compared to the murine knockout is noteworthy, and that the potential role of RhoH in B cell malignancy "remains largely unexplored."
- The authors note that Rac isoform functions and cross-compensation "may well differ depending on the cell type and species," and that the TCR signaling defect in RHOH-deficient patients "may contribute but likely does not sufficiently explain" the localized EV-HPV susceptibility.
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45 Not checked yet · 37 No full text of the sources · 18 Own result · 14 Own interpretation · 13 Check pending · 1 Supported so far
In the paper
“the genetic knock-out of Rac2 and later the conditional knock-out of Rac1 allowed us and others to demonstrate that in phagocytic cells Rac1 and Rac2 are differentially required for both chemotaxis and generation of phagocytic oxidants needed for bacterial killing56,60,24.”
§ Hematopoietic-specific Rho GTPases Rac2 and RhoH and human blood disorders > The Rac2 knock-out mouse model
What the sources say
- Check pendingcites [56] Roberts, 1999, Deficiency of the hematopoietic cell-specific Rho family GTPase Rac2 is characterized by abnormalities in neutrophil function and host defense, Immunity source
- Not checked — no full text of the sourcecites [60] Gu, 2002, RAC2 GTPase deficiency and myeloid cell dysfunction in human and mouse, J. Pediatr. Hematol. Oncol. source
- Not checked — no full text of the sourcecites [24] Filippi, 2004, Localization of Rac2 via the C terminus and aspartic acid 150 specifies superoxide generation, actin polarity and chemotaxis in neutrophils, Nat. Immunol. source
boostedstates a cause- Asserted: passes — The authors put it forward as true.
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In the paper
“Interestingly, T cell numbers are markedly reduced in Rac1 and 2 double knockout animals”
§ Hematopoietic-specific Rho GTPases Rac2 and RhoH and human blood disorders > The Rac2 knock-out mouse model
What the sources say
- Check pendingcites [62] Guo, 2008, Rac GTPase isoforms Rac1 and Rac2 play a redundant and crucial role in T-cell development, Blood source
plainstates a cause- Asserted: passes — The authors put it forward as true.
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In the paper
“Rac2−/− HSC/P cells exhibit a cell-intrinsic defect in microenvironment interaction that leads to defective long-term engraftment in competitive and secondary transplantation assays61.”
§ Hematopoietic-specific Rho GTPases Rac2 and RhoH and human blood disorders > The Rac2 knock-out mouse model
What the sources say
- Not checked — no full text of the sourcecites [61] Jansen, 2005, Rac2-deficient hematopoietic stem cells show defective interaction with the hematopoietic microenvironment and long-term engraftment failure, Stem cells (Dayton, Ohio) source
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In the paper
“In addition, these mice have an increased susceptibility to invasive fungal infections”
§ Hematopoietic-specific Rho GTPases Rac2 and RhoH and human blood disorders > The Rac2 knock-out mouse model
What the sources say
- Not checked yetcites [56] Roberts, 1999, Deficiency of the hematopoietic cell-specific Rho family GTPase Rac2 is characterized by abnormalities in neutrophil function and host defense, Immunity source
plainstates a cause- Asserted: passes — The authors put it forward as true.
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In the paper
“We have recently demonstrated that lack of RhoH expression also influences Rac and RhoA activity as well as their membrane localization in hematopoietic stem / progenitor cells (HSC / P) and leukemia cells”
§ Hematopoietic-specific Rho GTPases Rac2 and RhoH and human blood disorders > Cross-talk between Rho GTPases
What the sources say
- Not checked yetcites [37] Chae, 2008, Cross-talk between RhoH and Rac1 in regulation of actin cytoskeleton and chemotaxis of hematopoietic progenitor cells, Blood source
- Not checked yetcites [38] Troeger, 2012, RhoH is critical for cell-microenvironment interactions in chronic lymphocytic leukemia in mice and humans, Blood source
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Claims other papers make about this one
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In the citing paper
“In Rac2 2/2 mice, T-cell development occurs normally, most likely from functional redundancy between Rac1 and Rac2.37”
From Dominant activating RAC2 mutation with lymphopenia, immunodeficiency, and cytoskeletal defects (2019) · cites this paper as [37]
In the citing paper
“RhoH is frequently mutated in lymphomas and leukemias and mutations often correlate with prognosis, either poor or favorable, depending on the specific malignancy, precluding a role for RhoH as classical tumor suppressor or oncogene. 19”
From RhoH is a negative regulator of eosinophilopoiesis (2016) · cites this paper as [19]
In the citing paper
“This atypical Rho GTPase lacks intrinsic GTPase activity and remains in a constitutively active, GTPbound state [2,5].”
From Deletion of murine Rhoh leads to de-repression of Bcl-6 via decreased KAISO levels and accelerates a malignancy phenotype in a murine model of lymphoma (2022) · cites this paper as [5]
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Metadata
- Authors
- Troeger, A., & Williams, D. A.
- Affiliations
- Heinrich Heine University Düsseldorf (DE)
- Boston Children's Hospital (US)
- Corresponding author
- Williams, David A.
- Venue
- Experimental Cell Research
- Publisher
- Elsevier BV
- Published
- 2013-09
- Volume
- 319
- Issue
- 15
- Pages
- 2375-2383
- ISSN
- 0014-4827 (ISSN-L)
- PMC
- PMC3997055
- OpenAlex
- W2031545497
- Cited by
- 73
- References
- 79
- Citations by year
- 2025: 5 · 2024: 5 · 2023: 3 · 2022: 10 · 2021: 5 · 2020: 8 · 2019: 8 · 2018: 5 · 2017: 7 · 2016: 7 · 2015: 6 · 2014: 4
- FWCI
- 0.51
- Type
- journal article
- Language
- en
- Open access
- green
- pmc.ncbi.nlm.nih.gov
- Locations
- Experimental Cell Research (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- Funders
- National Institutes of Health (U54TR001005)
- National Cancer Institute (R01CA113969)
- National Center for Advancing Translational Sciences
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Kinase Regulation and GTPase Signaling
- Life Sciences › Immunology and Microbiology › Immunology › Immunodeficiency and Autoimmune Disorders
- Health Sciences › Medicine › Hematology › Platelet Disorders and Treatments
- Keywords
- Rho GTPases, Rac2, RhoH, hematopoietic cells, immunodeficiency, mouse knockout models, hematologic disorders
- MeSH terms
- RAC2 GTP-Binding Protein, Actins, Animals, Cytoskeleton, Gene Expression Regulation, Hematologic Diseases, Hematopoiesis, Humans, Mutation, Transcription Factors, Signal Transduction, Mice, Knockout, rho GTP-Binding Proteins, rac GTP-Binding Proteins, Myeloid Cells, Mice
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Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
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