Dysregulated RASGRP1 expression through RUNX1 mediated transcription promotes autoimmunity

Baars, Matthijs J.D.; Douma, Thera; Simeonov, Dimitre R.; Myers, David E.; Kulhanek, Kayla; Banerjee, Saikat; Zwakenberg, Susan; Baltissen, Marijke P; Amini, Mojtaba; Roock, Sytze de; Wijk, Femke van; Vermeulen, Michiel; Marson, Alexander; Roose, Jeroen P.; Vercoulen, Yvonne

doi:10.1002/eji.201948451

Cited by 13 publications

(10 citation statements)

References 44 publications

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“…It is believed that aberrant expression of RASGRP1 plays an important part in the development of autoimmunity. According to Baars et al [ 33 ], dysregulation of RASGRP1 often takes place in activated T cells and may, in a dose-dependent way, affect TCR-induced signaling as well as thymocyte selection. The immune response hypothesis of IC/BPS etiology [ 27 ], which is partly explained by this finding, suggests that RASGRP1 may have potential significance to the immunological environment of IC/BPS.…”

Section: Discussionmentioning

confidence: 99%

Identification of Immune-Related Genes and Small-Molecule Drugs in Interstitial Cystitis/Bladder Pain Syndrome Based on the Integrative Machine Learning Algorithms and Molecular Docking

Jiang

Xinqing

Al-Danakh

et al. 2022

Journal of Immunology Research

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Background. Interstitial cystitis/bladder pain syndrome (IC/BPS) is a chronic, severely distressing clinical syndrome characterized by bladder pain and pressure perceptions. The origin and pathophysiology of IC/BPS are currently unclear, making it difficult to diagnose and formulate successful treatments. Our study is aimed at investigating the role of immune-related genes in the diagnosis, progression, and therapy of IC/BPS. Method. The gene expression datasets GSE11783, GSE11839, GSE28242, and GSE57560 were retrieved from the GEO database for further analysis. Immune-related IC/BPS differentially expressed genes (DEGs) were identified by limma. Three distinct machine learning approaches, least absolute shrinkage and selection operator (LASSO), support vector machine–recursive feature elimination (SVM-RFE), and random forest (RF), were used to find the immune-related IC characteristic genes. Nomogram and receiving operator curves (ROC) were plotted to measure characteristic effectiveness. Using the CMap database and the molecular docking approach, potential small-molecule medicines were found and verified. Consensus cluster analysis was also performed to separate the IC/BPS samples into immunological subtypes. Results. A total of 24 immune-related IC/BPS-DEGs were identified. When compared to the normal control group, the IC/BPS cohort had significantly more immune cell infiltration. Integrative machine learning methods discovered 5 IC/BPS characteristic genes (RASGRP1, PPBP, RBP4, CR2, and PROS2) that may predict IC/BPS diagnosis and immune cell infiltration. Furthermore, two immunological subgroups with substantial variations in immune cell infiltration across IC/BPS samples were identified, which were named cluster1 and cluster2, with the hallmark genes having greater expression in cluster2. Finally, bumetanide was shown to have the potential to be a medication for the treatment of IC/BPS, and it performed well in terms of its molecular binding with RASGRP1. Conclusion. We found and validated 5 immune-related IC/BPS genes (RASGRP1, PPBP, RBP4, CR2, and PROS2) and 2 IC/BPS immune subtypes. In addition, bumetanide was discovered to be a potential drug for treating IC/BPS, which may provide new insight into the diagnosis and immune therapy of IC/BPS patients.

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Section: Discussionmentioning

confidence: 99%

Identification of Immune-Related Genes and Small-Molecule Drugs in Interstitial Cystitis/Bladder Pain Syndrome Based on the Integrative Machine Learning Algorithms and Molecular Docking

Jiang

Xinqing

Al-Danakh

et al. 2022

Journal of Immunology Research

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“…For example, it was shown that suppressing RasGRP1 inhibited neuroinflammation [ 25 ]. Additionally, Baars et al showed that decreased RasGRP1 reduced active inflammatory disease [ 26 ]. However, the impact of RasGRP1 on sepsis-induced AKI is still unclear.…”

Section: Discussionmentioning

confidence: 99%

RasGRP Exacerbates Lipopolysaccharide-Induced Acute Kidney Injury Through Regulation of ERK Activation

Tang

Wang

Liu

et al. 2022

Open Forum Infectious Diseases

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Background Excessive inflammatory activities are reported to be the primary cause of sepsis-induced acute kidney injury (AKI). Ras guanyl nucleotide releasing protein (RasGRP) could prevent inflammatory response. However, its role in the regulation of inflammatory response in sepsis-associated AKI remains unclear. Methods Wild-type or RasGRP1 deficiency mice were treated with lipopolysaccharides intraperitoneally in combination with D-galactosamine to establish a mouse model of sepsis-associated AKI. Serum inflammatory cytokines were measured using ELISA. The mRNA levels of Il6, Tnf, Nos2, and Il1b were measured using q-RT-PCR. The morphological change in kidney tubule was determined by hematoxylin and eosin staining. The protein levels of RasGRP, Erk1/2, and Jnk were determined using Western blot. Results RasGRP1 mRNA and protein levels were significantly increased in patients with sepsis-related AKI compared to those in healthy subjects. RasGRP knockout markedly reduced inflammatory cytokines induced by AKI in sepsis when compared with wild-type mice. Additionally, RasGRP deficiency inhibited the phosphorylation of ERK1/2 without altering Jnk expression. In conclusion, we demonstrate that RasGRP1 plays a pivotal role in sepsis-associated AKI. Downregulation of RasGRP1 could significantly inhibit inflammatory response by inhibiting the activation of ERK1/2 and MAPK pathway, thereby reducing AKI induced by sepsis. Conclusion Our data suggest that RasGRP exacerbates lipopolysaccharides-induced acute kidney injury through regulating ERKs activation, which reveals a potential therapeutic target for the treatment of sepsis-induced AKI.

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“…Interestingly, humans deficient in RasGRP1 have increased numbers of TCRγδ+ CD8+ T cells [ 58 ]. RasGRP1-deficient mice develop splenomegaly and autoantibodies as a result of T cell dysregulation, characterized by an elevated interleukin (IL)-4 secretion [ 31 , 59 , 60 , 61 ]. This elevation in IL-4 drives B cell proliferation and the production of autoantibodies [ 60 ].…”

Section: Rasgrp1: Cell Development and Functionmentioning

confidence: 99%

“…This elevation in IL-4 drives B cell proliferation and the production of autoantibodies [ 60 ]. Furthermore, one study found that the binding of RUNX1 to a putative autoimmunity-associated enhancer 1 upstream of Rasgrp1 mediates the RasGRP1 deficiency-mediated autoimmune disease [ 61 ].…”

Section: Rasgrp1: Cell Development and Functionmentioning

confidence: 99%

A Focused Review of Ras Guanine Nucleotide-Releasing Protein 1 in Immune Cells and Cancer

Hsu

Rodrigues

Winer

et al. 2023

IJMS

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Four Ras guanine nucleotide-releasing proteins (RasGRP1 through 4) belong to the family of guanine nucleotide exchange factors (GEFs). RasGRPs catalyze the release of GDP from small GTPases Ras and Rap and facilitate their transition from an inactive GDP-bound to an active GTP-bound state. Thus, they regulate critical cellular responses via many downstream GTPase effectors. Similar to other RasGRPs, the catalytic module of RasGRP1 is composed of the Ras exchange motif (REM) and Cdc25 domain, and the EF hands and C1 domain contribute to its cellular localization and regulation. RasGRP1 can be activated by a diacylglycerol (DAG)-mediated membrane recruitment and protein kinase C (PKC)-mediated phosphorylation. RasGRP1 acts downstream of the T cell receptor (TCR), B cell receptors (BCR), and pre-TCR, and plays an important role in the thymocyte maturation and function of peripheral T cells, B cells, NK cells, mast cells, and neutrophils. The dysregulation of RasGRP1 is known to contribute to numerous disorders that range from autoimmune and inflammatory diseases and schizophrenia to neoplasia. Given its position at the crossroad of cell development, inflammation, and cancer, RASGRP1 has garnered interest from numerous disciplines. In this review, we outline the structure, function, and regulation of RasGRP1 and focus on the existing knowledge of the role of RasGRP1 in leukemia and other cancers.

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Dysregulated RASGRP1 expression through RUNX1 mediated transcription promotes autoimmunity

Cited by 13 publications

References 44 publications

Identification of Immune-Related Genes and Small-Molecule Drugs in Interstitial Cystitis/Bladder Pain Syndrome Based on the Integrative Machine Learning Algorithms and Molecular Docking

Identification of Immune-Related Genes and Small-Molecule Drugs in Interstitial Cystitis/Bladder Pain Syndrome Based on the Integrative Machine Learning Algorithms and Molecular Docking

RasGRP Exacerbates Lipopolysaccharide-Induced Acute Kidney Injury Through Regulation of ERK Activation

A Focused Review of Ras Guanine Nucleotide-Releasing Protein 1 in Immune Cells and Cancer

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