RhoH/TTF Negatively Regulates Leukotriene Production in Neutrophils

Daryadel, Arezoo; Yousefi, Shída; Troi, David; Schmid, Inès; Schmidt-Mende, Jan; Mordasini, Carlo; Dahinden, Clemens A.; Ziemiecki, Andrew; Simon, Hans‐Uwe

doi:10.4049/jimmunol.0803846

Cited by 15 publications

(22 citation statements)

References 41 publications

(47 reference statements)

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“…1). Freshly isolated neutrophils did not express detectable RhoH protein, confirming earlier work demonstrating that RhoH expression in these cells depends on GM-CSF stimulation [2,9]. Like neutrophils, blood monocytes from healthy individuals did not express detectable RhoH protein (Fig.…”

Section: Resultssupporting

confidence: 76%

“…Immunoblotting analyses using an anti-RhoH Ab, which was recently generated in our laboratory [2], revealed that RhoH was detectable at the expected molecular weight of 21 kDa in PBMC lysates and in highly purified T-and B-cell lysates (Fig. 1).…”

Section: Resultsmentioning

confidence: 99%

“…Anti-RhoH serum was generated in our laboratory [2]. For cell isolation, we used FITC-conjugated anti-CD4, APC-conjugated anti-CD8, FITCconjugated anti-CD14, and PE-conjugated anti-CD19 mAb from BD Biosciences as well as secondary mAb microbeads from Miltenyi Biotec GmbH (Bergisch Gladbach, Germany).…”

Section: Reagentsmentioning

confidence: 99%

“…RhoH mRNA expression was reported to be restricted to hematopoietic cells [1]. Protein expression data are not available, except for one recent report, which demonstrated increased RhoH protein expression in GM-CSF-stimulated neutrophils [2].…”

Section: Introductionmentioning

confidence: 99%

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Lysosomal degradation of RhoH protein upon antigen receptor activation in T but not B cells

et al. 2010

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RhoH is a member of the Rho (ras homologous) GTPase family, yet it lacks GTPase activity and thus remains in its active conformation. Unlike other Rho GTPases, the RhoH gene transcript is restricted to hematopoietic cells and RhoH was shown to be required for adequate T-cell activation through the TCR. Here, we demonstrate that both blood T and B cells, but not neutrophils or monocytes, express RhoH protein under physiological conditions. Upon TCR complex activation, RhoH was degraded in lysosomes of primary and Jurkat T cells. Pharmacologic activation of T cells distal to the TCR complex had no effect on RhoH protein levels suggesting that early events during T-cell activation are required for RhoH protein degradation. In contrast to T cells, activation of the BCR in blood B cells was not associated with changes in RhoH levels. These data suggest that RhoH function might be regulated by lysosomal degradation of RhoH protein following TCR complex but not BCR activation. This newly discovered regulatory pathway of RhoH expression might limit TCR signaling and subsequent T-cell activation upon Ag contact.

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Section: Resultssupporting

confidence: 76%

Section: Resultsmentioning

confidence: 99%

Section: Reagentsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Lysosomal degradation of RhoH protein upon antigen receptor activation in T but not B cells

et al. 2010

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“…Moreover, although RHOH is normally expressed in all leukocytes, the T cell phenotype is clearly the strongest phenotype in mice and humans lacking RHOH. Rhoh -/-mice have a mild myeloid phenotype (39,40); no overt myeloid phenotype was observed in our patients. Moreover, none of the known patients with myeloid PIDs, including disorders affecting mononuclear or polymorphonuclear phagocytes, display persistent EV-HPV infections (41,42).…”

Section: Discussionmentioning

confidence: 97%

Human RHOH deficiency causes T cell defects and susceptibility to EV-HPV infections

Crequer¹,

Troeger²,

Patin³

et al. 2012

J. Clin. Invest.

137

102

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Epidermodysplasia verruciformis (EV) is a rare genetic disorder characterized by increased susceptibility to specific human papillomaviruses, the betapapillomaviruses. These EV-HPVs cause warts and increase the risk of skin carcinomas in otherwise healthy individuals. Inactivating mutations in epidermodysplasia verruciformis 1 (EVER1) or EVER2 have been identified in most, but not all, patients with autosomal recessive EV. We found that 2 young adult siblings presenting with T cell deficiency and various infectious diseases, including persistent EV-HPV infections, were homozygous for a mutation creating a stop codon in the ras homolog gene family member H (RHOH) gene. RHOH encodes an atypical Rho GTPase expressed predominantly in hematopoietic cells. Patients' circulating T cells contained predominantly effector memory T cells, which displayed impaired TCR signaling. Additionally, very few circulating T cells expressed the β 7 integrin subunit, which homes T cells to specific tissues. Similarly, Rhoh-null mice exhibited a severe overall T cell defect and abnormally small numbers of circulating β 7 -positive cells. Expression of the WT, but not of the mutated RHOH, allele in Rhoh -/-hematopoietic stem cells corrected the T cell lymphopenia in mice after bone marrow transplantation. We conclude that RHOH deficiency leads to T cell defects and persistent EV-HPV infections, suggesting that T cells play a role in the pathogenesis of chronic EV-HPV infections.

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Rhoh deficiency reduces peripheral T‐cell function and attenuates allogenic transplant rejection

et al. 2010

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Rhoh is a hematopoietic system-specific GTPase. Rhoh-deficient T cells have been shown to have a defect in TCR signaling manifested during their thymic development. Our aims were to investigate the phenotype of peripheral Rhoh-deficient T cells and to explore in vivo the potential benefit of Rhoh deficiency in a clinically relevant situation, in which T-cell inhibition is desirable. In murine allogenic kidney transplantation, Rhoh deficiency caused a significant 75% reduction of acute and chronic transplant rejection accompanied by 75% lower alloantigen-specific antibody levels and significantly better graft function. This effect was independent of the lower T-cell numbers in Rhoh-deficient recipients, because injection of equal numbers of Rhoh-deficient or control T cells into kidney transplanted mice with SCID led again to a significant 60% reduction of rejection. Mixed lymphocyte reaction revealed that the weaker alloreactivity was associated with a 85% lower cytotoxicity and a 50-80% lower cytokine release in Rhoh-deficient T cells without an influence on the secretion itself. Antigen uptake and presentation in DC were unaffected by Rhoh deficiency. These findings stress the importance of Rhoh for the function of peripheral T cells.Key words: Animal models . T cell . Transplantation IntroductionRas homolog gene family, member H (Rhoh) (previous name: translocation three four) is a member of the large family of the small monomeric GTPases, which are intracellular plasma membrane-bound signaling molecules, exerting regulatory functions in a wide variety of cellular processes such as cytoskeleton organization, cell polarization, vesicle formation and transport as well as proliferation. These intracellular switches cycle between two functional states: in the active state (GTP bound), they are able to interact with downstream effector molecules and thus generate a response until their intrinsic GTPase activity hydrolyzes the bound GTP and thereby returns them into an inactive (GDP bound) state. The group of small monomeric GTPases encompasses five major families: Arf, Rab, Ran, Ras and Rho (Ras homolog); the latter consisting of Rho-, Rac-and Cdc42-subfamilies [1]. The hematopoietic-specific Rho GTPase, Rhoh, was initially described as a fusion transcript resulting from chromosomal translocation t(3, 4) (hence, the former name ''translocation three four'') in several cases of B-cell diffuse large cell lymphoma and multiple myeloma [2][3][4]. Further investigations confirmed the restriction of Rhoh expression to hematopoiesis-related organs (BM, thymus and spleen) and in particular to hematopoietic progenitor cells as well as fully differentiated myeloid and lymphoid cells [5]. In contrast to most other small Ã These authors have contributed equally to this study. Although recently a substantial progress has been achieved in the treatment of acute rejection of transplanted organs, the adverse effects of the current immunosuppressive drugs and chronic transplant dysfunction represent unresolved clinical problems. A...

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RhoH/TTF Negatively Regulates Leukotriene Production in Neutrophils

Cited by 15 publications

References 41 publications

Lysosomal degradation of RhoH protein upon antigen receptor activation in T but not B cells

Lysosomal degradation of RhoH protein upon antigen receptor activation in T but not B cells

Human RHOH deficiency causes T cell defects and susceptibility to EV-HPV infections

Rhoh deficiency reduces peripheral T‐cell function and attenuates allogenic transplant rejection

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