Pax5 regulates B cell immunity by promoting PI3K signaling via PTEN down-regulation

Calderón, Lesly; Schindler, Karina; Malin, Stephen; Schebesta, Alexandra; Sun, Qiong; Schwickert, Tanja A.; Alberti, Chiara; Fischer, Maria; Jaritz, Markus; Tagoh, Hiromi; Ebert, Anja; Minnich, Martina; Liston, Adrian; Cochella, Luisa; Busslinger, Meinrad

doi:10.1126/sciimmunol.abg5003

Cited by 37 publications

(32 citation statements)

References 90 publications

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“…Immunization with the T cell–dependent antigen NP-keyhole limpet hemocyanin (NP-KLH) in the adjuvant alum demonstrated that no germinal center (GC) B cells were generated in the spleen of Pax5 R31Q/− mice on day 14 after immunization ( Fig. 4 E ), similar to the absence of GC B cells in response to conditional Pax5 deletion in mature B cells ( Calderón et al, 2021 ). Consequently, NP-specific plasma cells were strongly reduced in the spleen of Pax5 R31Q/− mice ( Fig.…”

Section: Resultsmentioning

confidence: 95%

“…PAX5 is well known for its role in B cell immunity ( Calderón et al, 2021 ; Horcher et al, 2001 ; Nutt et al, 1999 ) and its function as a haploinsufficient tumor suppressor gene in B cell acute lymphoblastic leukemia ( Gu et al, 2019 ; Mullighan et al, 2007 ). Here, we identified new functions of Pax5 in controlling cerebellar development and the neurogenesis of GABAergic midbrain neurons and demonstrated a causative involvement of PAX5 deficiency in ASD etiology.…”

Section: Discussionmentioning

confidence: 99%

“…Pax5 mutant mice exhibit abnormal morphogenesis of the posterior midbrain and anterior cerebellum ( Urbánek et al, 1994 ), while both the midbrain and cerebellum fail to develop in Pax2 , Pax5 double-mutant embryos due to lack of the isthmic organizer ( Schwarz et al, 1997 ). Within the hematopoietic system, Pax5 is exclusively expressed in the B lymphoid lineage ( Fuxa and Busslinger, 2007 ), where it functions as an essential regulator of B cell commitment ( Nutt et al, 1999 ), development ( Horcher et al, 2001 ), and immunity ( Calderón et al, 2021 ). At the molecular level, Pax5 performs a dual role in B lymphopoiesis by acting as a transcriptional repressor to suppress B lineage–inappropriate genes ( Delogu et al, 2006 ; Revilla-i-Domingo et al, 2012 ) and as an activator to induce gene expression required for B cell development and function ( Revilla-i-Domingo et al, 2012 ; Schebesta et al, 2007 ).…”

Section: Introductionmentioning

confidence: 99%

“…At the molecular level, Pax5 performs a dual role in B lymphopoiesis by acting as a transcriptional repressor to suppress B lineage–inappropriate genes ( Delogu et al, 2006 ; Revilla-i-Domingo et al, 2012 ) and as an activator to induce gene expression required for B cell development and function ( Revilla-i-Domingo et al, 2012 ; Schebesta et al, 2007 ). In mature B cells, Pax5 additionally promotes phosphoinositide 3-kinase (PI3K) signaling by down-regulating expression of the phosphatase and tensin homolog (PTEN) protein, a negative regulator of this pathway ( Calderón et al, 2021 ). Another important function of Pax5 is to suppress B cell tumorigenesis in mice ( Cobaleda et al, 2007 ) and humans ( Mullighan et al, 2007 ), where heterozygous PAX5 mutations prominently contribute to the development of B cell acute lymphoblastic leukemia ( Gu et al, 2019 ).…”

Section: Introductionmentioning

confidence: 99%

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Biallelic PAX5 mutations cause hypogammaglobulinemia, sensorimotor deficits, and autism spectrum disorder

Kaiser

Gruenbacher

Oyaga

et al. 2022

Journal of Experimental Medicine

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The genetic causes of primary antibody deficiencies and autism spectrum disorder (ASD) are largely unknown. Here, we report a patient with hypogammaglobulinemia and ASD who carries biallelic mutations in the transcription factor PAX5. A patient-specific Pax5 mutant mouse revealed an early B cell developmental block and impaired immune responses as the cause of hypogammaglobulinemia. Pax5 mutant mice displayed behavioral deficits in all ASD domains. The patient and the mouse model showed aberrant cerebellar foliation and severely impaired sensorimotor learning. PAX5 deficiency also caused profound hypoplasia of the substantia nigra and ventral tegmental area due to loss of GABAergic neurons, thus affecting two midbrain hubs, controlling motor function and reward processing, respectively. Heterozygous Pax5 mutant mice exhibited similar anatomic and behavioral abnormalities. Lineage tracing identified Pax5 as a crucial regulator of cerebellar morphogenesis and midbrain GABAergic neurogenesis. These findings reveal new roles of Pax5 in brain development and unravel the underlying mechanism of a novel immunological and neurodevelopmental syndrome.

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Section: Resultsmentioning

confidence: 95%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

Biallelic PAX5 mutations cause hypogammaglobulinemia, sensorimotor deficits, and autism spectrum disorder

Kaiser

Gruenbacher

Oyaga

et al. 2022

Journal of Experimental Medicine

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“…The deletion of PTEN can increase the threshold of neutrophils’ response to chemokines and reduce neutrophil-mediated inflammation to a certain extent ( Billadeau, 2008 ). In addition, PTEN inhibits the differentiation of B cells into plasma cells by regulating PI3K Signal transduction ( Calderón et al, 2021 ). Zhu et al (2021) found that miR-520b targeting PTEN promoted the polarization of M0 macrophages toward M2 in breast cancer.…”

Section: Discussionmentioning

confidence: 99%

Construction and Bioinformatics Analysis of circRNA-miRNA-mRNA Network in Acute Myocardial Infarction

Zhou

Wang

et al. 2022

Front. Genet.

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Background: Acute myocardial infarction (AMI) is one of the main fatal diseases of cardiovascular diseases. Circular RNA (circRNA) is a non-coding RNA (ncRNA), which plays a role in cardiovascular disease as a competitive endogenous RNA (ceRNA). However, their role in AMI has not been fully clarified. This study aims to explore the mechanism of circRNA-related ceRNA network in AMI, and to identify the corresponding immune infiltration characteristics.Materials and Methods: The circRNA (GSE160717), miRNA (GSE24548), and mRNA (GSE60993) microarray datasets of AMI were downloaded from the Gene Expression Omnibus (GEO) database. Differentially expressed circRNAs (DEcircRNAs), miRNAs (DEmiRNAs), and mRNAs (DEmRNAs) were identified by the “limma” package. After integrating the circRNA, miRNA and mRNA interaction, we constructed a circRNA-miRNA-mRNA network. The “clusterProfiler” package and String database were used for functional enrichment analysis and protein-protein interaction (PPI) analysis, respectively. After that, we constructed a circRNA-miRNA-hub gene network and validated the circRNAs and mRNAs using an independent dataset (GSE61144) as well as qRT-PCR. Finally, we used CIBERSORTx database to analyze the immune infiltration characteristics of AMI and the correlation between hub genes and immune cells.Results: Using the “limma” package of the R, 83 DEcircRNAs, 54 DEmiRNAs, and 754 DEmRNAs were identified in the microarray datasets of AMI. Among 83 DEcircRNAs, there are 55 exonic DEcircRNAs. Then, a circRNA-miRNA-mRNA network consists of 21 DEcircRNAs, 11 DEmiRNAs, and 106 DEmRNAs were predicted by the database. After that, 10 hub genes from the PPI network were identified. Then, a new circRNA-miRNA-hub gene network consists of 14 DEcircRNAs, 7 DEmiRNAs, and 9 DEmRNAs was constructed. After that, three key circRNAs (hsa_circ_0009018, hsa_circ_0030569 and hsa_circ_0031017) and three hub genes (BCL6, PTGS2 and PTEN) were identified from the network by qRT-PCR. Finally, immune infiltration analysis showed that hub genes were significantly positively correlated with up-regulated immune cells (neutrophils, macrophages and plasma cells) in AMI.Conclusion: Our study constructed a circRNA-related ceRNA networks in AMI, consists of hsa_circ_0031017/hsa-miR-142-5p/PTEN axis, hsa_circ_0030569/hsa-miR-545/PTGS2 axis and hsa_circ_0009018/hsa-miR-139-3p/BCL6 axis. These three hub genes were significantly positively correlated with up-regulated immune cells (neutrophils, macrophages and plasma cells) in AMI. It helps improve understanding of AMI mechanism and provides future potential therapeutic targets.

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Comprehensive analysis of clinical prognosis and biological significance of CNIH4 in cervical cancer

Wang,

Wang

et al. 2023

Cancer Medicine

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BackgroundCornichon homolog 4 (CNIH4) belongs to the CNIH family. It functions as an oncogene in many tumors. However, CNIH4's significance in the immune landscape and its predictive potential in cervical cancer (CESC) is unexplored.MethodsCNIH4 levels and its effect on the survival of patients with CESC were evaluated using data retrieved from The Cancer Genome Atlas (TCGA). The oncogenic effect of CNIH4 in CESC was determined using small interfering RNA‐mediated transfected cell lines and tumorigenesis experiments in animal models.ResultsHigher expression of CNIH4 was found in advanced tumor and pathological stages, as well as lymph node metastasis. CNIH4 expression correlated positively with the infiltration of macrophages M2 and resting dendritic cells into the affected tissue. Additionally, functional enrichment of RNA‐sequencing of CNIH4‐knocked down CESC cell lines showed the association of CNIH4 to the PI3K‐Akt signaling pathway. Single‐sample gene set enrichment analysis highlighted several immune pathways that were elevated in the CESC samples with enhanced levels of CNIH4, including Type‐I and Type‐II IFN‐response pathways. The impact of CNIH4 on drug sensitivity was further assessed using the GDSC database. As CNIH4 is linked to the immune landscape in CESC, this study determined a four‐gene risk prediction signature utilizing CNIH4‐related immunomodulators. The risk score quantified from the prediction signature was an independent predictive indicator in CESC. Receiver operating characteristic curve analysis verified the good predictive ability of the four‐gene signature in TCGA‐CESC cohort. Thus, the CNIH4‐related model showed potential as an auxiliary TNM staging system tool.ConclusionCNIH4 may be an effective predictive biomarker for patients with cervical cancer, thus providing new ideas and research directions for CESC.

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Pax5 regulates B cell immunity by promoting PI3K signaling via PTEN down-regulation

Cited by 37 publications

References 90 publications

Biallelic PAX5 mutations cause hypogammaglobulinemia, sensorimotor deficits, and autism spectrum disorder

Biallelic PAX5 mutations cause hypogammaglobulinemia, sensorimotor deficits, and autism spectrum disorder

Construction and Bioinformatics Analysis of circRNA-miRNA-mRNA Network in Acute Myocardial Infarction

Comprehensive analysis of clinical prognosis and biological significance of CNIH4 in cervical cancer

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