The Poly(C)-binding protein Pcbp2 is essential for CD4+ T cell development and proliferation.
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA808733 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR18079746_1.fastq.gz | Fastqsanger.gz | |||
| SRR18079746_2.fastq.gz | Fastqsanger.gz | |||
| SRR18079747_1.fastq.gz | Fastqsanger.gz | |||
| SRR18079747_2.fastq.gz | Fastqsanger.gz | |||
| SRR18079748_1.fastq.gz | Fastqsanger.gz |
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Project description:Defining the molecular mechanisms that impact T cell maturation and function is important because abnormalities in these processes can lead to immunodeficient states or autoimmunity. RNA-binding proteins (RBPs) have emerged as critical factors in thymopoiesis, immune cell lineage commitment and maintenance, and as modulators of immune responses. The RBP paralogs Pcbp1 and Pcbp2 are widely expressed in the innate and adaptive immune systems and are each essential for mouse development. Pcbp1 has been shown to prevent conversion of CD4+ effector T cells into Foxp3+ regulatory T cells (Treg), with loss of Pcbp1 resulting in increased Treg differentiation. To determine whether Pcbp2 also is required for CD4+ T cell development and function, we derived mice with conditional Pcbp2 deletion in CD4+ T cells and assessed their overall phenotype and proliferative responses to activating stimuli. We found that Pcbp2 is essential for CD4+ T conventional cell (Tconv) proliferation, working through regulation of CD4 receptor co-stimulatory signaling. In addition, our data demonstrate a clear association between Pcbp2 control of Runx1 exon 6 splicing in CD4+ T cells and a specific role for Pcbp2 in the maintenance of peripheral CD4+ lymphocyte population size. Pcbp2 deficiency in the CD4+ lineage did not impact Treg abundance in vivo or function in vitro. Last, we show that Pcbp2 function is required for optimal in vivo Tconv cell activation in a T cell adoptive transfer colitis model system. These data lead us to conclude that Pcbp2 is a critical regulator of T cell signaling and function in the CD4+ lineage.
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Project description:RNA-binding proteins participate in a complex array of post-transcriptional controls essential to cell-type specification and somatic development. Despite their detailed biochemical characterizations, the degree to which each RNA-binding protein impacts on mammalian embryonic development remains incompletely defined and the level of functional redundancy among subsets of these proteins remains open to question. The poly-(C) binding proteins, Pcbp's (aCPs, hnRNPEs), are encoded by a highly conserved and broadly expressed gene family. The two major Pcbp isoforms, Pcbp2 and Pcbp1, are robustly expressed in a wide range of tissues and exert both nuclear and cytoplasmic controls over gene expression. Here we report that Pcbp1-null embryos are rendered nonviable in the peri-implantation stage. In contrast, Pcbp2-null embryos survive until mid-gestation at which time they undergo a loss in viability associated with cardiovascular and hematopoietic abnormalities. Adult mice heterozygous for either Pcbp1 or Pcbp2 null alleles display a mild and non-disruptive growth defect. These data reveal that Pcbp1 and Pcbp2 are individually essential for mouse embryonic development and post-natal growth, reveal a non-redundant in vivo role for Pcpb2 in hematopoiesis, and provide direct evidence that Pcbp1, a retrotransposed derivative of Pcpb2, has evolved essential function(s) in the mammalian genome. mRNA-seq on fetal liver tissue from 12.5 days post coitum. 4 replicates of WT and 3 replicates of PCBP2 Knockout
2015-11-05 | E-GEOD-72491 | biostudies-arrayexpress
Project description:RNA-binding proteins participate in a complex array of post-transcriptional controls essential to cell-type specification and somatic development. Despite their detailed biochemical characterizations, the degree to which each RNA-binding protein impacts on mammalian embryonic development remains incompletely defined and the level of functional redundancy among subsets of these proteins remains open to question. The poly-(C) binding proteins, Pcbp’s (aCPs, hnRNPEs), are encoded by a highly conserved and broadly expressed gene family. The two major Pcbp isoforms, Pcbp2 and Pcbp1, are robustly expressed in a wide range of tissues and exert both nuclear and cytoplasmic controls over gene expression. Here we report that Pcbp1-null embryos are rendered nonviable in the peri-implantation stage. In contrast, Pcbp2-null embryos survive until mid-gestation at which time they undergo a loss in viability associated with cardiovascular and hematopoietic abnormalities. Adult mice heterozygous for either Pcbp1 or Pcbp2 null alleles display a mild and non-disruptive growth defect. These data reveal that Pcbp1 and Pcbp2 are individually essential for mouse embryonic development and post-natal growth, reveal a non-redundant in vivo role for Pcpb2 in hematopoiesis, and provide direct evidence that Pcbp1, a retrotransposed derivative of Pcpb2, has evolved essential function(s) in the mammalian genome.
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Project description:Alternative cleavage and polyadenylation (APA) is an important post-transcriptional regulatory mechanism, which could lead many diseases. PCBP2 plays critical roles in mRNA stabilization, translational enhancement and contributes to human cancer development and progression even though the molecular mechanism is not completely understood. Herein, we report that increased expression of PCBP2 is observed in human breast cancer tissues compared to benign or normal breast tissues, and high expression of PCBP2 is significantly associated with disease progression and poor outcome in patients with breast cancer. Knockdown of PCBP2 expression significantly decreased breast cancer cell proliferation, migration and invasion in vitro and in vivo. Molecularly, UFD1 and NT5E were identified as the downstream genes of PCBP2, which were scanned and verified based on RNA sequencing. Moreover, PCBP2 promotes oncogenic behaviors of breast cancer cells via upregulating the expression of UFD1 and NT5E by directly binding to their 3' untranslated regions (UTRs). Furthermore, we determine that the APA process is involved in regulating the overexpression PCBP2 in breast cancer cells. Therefore, our findings reveal that APA of PCBP2 3' UTR contributes to its overexpression and then promotes breast cancer progression by regulating the expression of UFD1 and NT5E.
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Project description:To mount an anti-pathogen response, CD4 T cells must undergo rapid cell proliferation. However, poorly controlled expansion can result in diseases such as autoimmunity. One important regulator of T cell activity is the E3 ubiquitin ligase Itch. Itch deficient patients suffer from extensive autoinflammation. Similarly, Itch deficient mice exhibit inflammation characterized by high numbers of activated CD4 T cells. While the role of Itch in limiting CD4 T cell cytokine production has been extensively studied, it is less clear whether and how Itch regulates proliferation of these cells. We determined that Itch deficient CD4 T cells are hyperproliferative in vitro and in vivo, due to increased S phase entry. Whole cell proteomics analysis of Itch deficient primary mouse CD4 T cells revealed increased abundance of the -catenin co-activator WW domain binding protein 2 (WBP2). Furthermore, Itch deficient cells demonstrate increased WBP2 protein stability, and Itch and WBP2 interact in CD4 T cells. Knockdown of WBP2 in CD4 T cells caused reduced proliferation. Together, our data support that Itch attenuates CD4 T cell proliferation by promoting WBP2 degradation. This study identifies novel roles for Itch and WBP2 in regulating CD4 T cell proliferation, providing insight into how Itch may prevent inflammation.
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Project description:The RNA-binding protein Pcbp2 is widely expressed in the innate and adaptive immune systems and is essential for mouse development. To determine whether Pcbp2 is required for CD4+ T cell development and function, we derived mice with conditional Pcbp2 deletion in CD4+ T cells and assessed their overall phenotype and proliferative responses to activating stimuli. We found that Pcbp2 is essential for T conventional cell (Tconv) proliferation, working through regulation of co-stimulatory signaling. Pcbp2 deficiency in the CD4+ lineage did not impact Treg abundance in vivo or function in vitro. In addition, our data demonstrate a clear association between Pcbp2 control of Runx1 exon 6 splicing in CD4+ T cells and a specific role for Pcbp2 in the maintenance of peripheral CD4+ lymphocyte population size. Last, we show that Pcbp2 function is required for optimal in vivo Tconv cell activation in a T cell adoptive transfer colitis model system.
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