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PCBP1 selectively binds to mRNA to regulate alternative splicing. (A) Venn diagram showed the overlap of PCBP1-bound peak’s genes and PCBP1-regulated alternatively splicing genes, and the PCBP1-bound peak’s genes is the union of two IP samples. LogP: log2 pvalue of enrichment terms. (B) Bar plot exhibited the most enriched GO biological process results of the overlap peak’s genes in figA, that making use of analyses by Metascape. (C) IGV-sashimi plot showed the UPF1-bound sites across mRNA of PML. The transcript of the gene was plotted at the bottom of the graph. (D) IGV-sashimi plot showed the UPF1-regulated alternative splicing events across mRNA of Pml. The transcript of the gene was plotted at the bottom of the graph and on the right was a model diagram of splicing events.
Source publication
Rheumatoid arthritis (RA) is an autoimmune disease characterized by persistent synovitis, in which T helper 1 (Th1) can promote the development of a pro-inflammatory microenvironment. Poly(rC)-binding protein 1 (PCBP1) has been identified as a promising biomarker of RA, while its molecular mechanisms in RA development are unknown. As a canonical RN...
Citations
... PCBP1 was found decreased in RA Th1 cells, and by silencing PCBP1 it is possible to exert an effect not only on the transcription of various proteins involved in the inflammatory response, but also on the levels and variety of alternative splicing in Th1 cells. Even if these results are po-tentially relevant in RA pathogenesis, additional studies are required in order to clarify the precise role of PCBP1 in the disease (48). It is well known that the amplification of inflammation and its perpetuation might be in part due to some changes in the cellular metabolism of the adaptive immune system. ...
Rheumatoid arthritis (RA) is a chronic autoimmune disease characterised by local and systemic inflammation. The complex interplay between immune cells and soluble mediators leads to the induction and perpetuation of aberrant inflammatory and autoimmune responses. The research carried out in the last year in the field of RA enabled the identification of new mechanisms involved in the pathogenesis of the disease and therefore unmasked new potential therapeutic targets. In this review article we summarised the new insights into RA pathogenesis from original research articles published in the last year.
... In addition to regulating intracellular iron trafficking, PCBPs are involved in posttranscriptional gene regulation, maintenance of mitochondrial stability, and are associated with a wide variety of pathophysiologies such as rheumatoid arthritis [37], amyotrophic lateral sclerosis (ALS) [38], and Huntington's disease (HD), and certain neurodevelopmental disorders [39]. Although the iron chaperone and RNA-binding functions of PCBPs have been shown to be independently essential [40], it is not clear how these functions potentially contribute to the pathogenesis of the above-mentioned disorders. ...
Systemic iron homeostasis needs to be tightly controlled, as both deficiency and excess iron cause major global health concerns, such as iron deficiency anemia, hemochromatosis, etc. In mammals, sufficient dietary acquisition is critical for fulfilling the systemic iron requirement. New questions are emerging about whether and how cellular iron transport pathways integrate with the iron storage mechanism. Ferritin is the intracellular iron storage protein that stores surplus iron after all the cellular needs are fulfilled and releases it in the face of an acute demand. Currently, there is a surge in interest in ferritin research after the discovery of novel pathways like ferritinophagy and ferroptosis. This review emphasizes the most recent ferritin-related discoveries and their impact on systemic iron regulation.
Purpose
This study aimed to elucidate the impact of upadacitinib, a Janus kinase 1 (JAK1)-specific inhibitor, on experimental autoimmune uveitis (EAU) and explore its underlying mechanisms.
Methods
We utilized single-cell RNA sequencing (scRNA-seq) and single-cell assay for transposase-accessible chromatin sequencing (scATAC-seq) to investigate the JAK/signal transducer and activator of transcription (STAT) pathway in peripheral blood mononuclear cells (PBMCs) of 12 patients with Vogt–Koyanagi–Harada (VKH) disease and cervical draining lymph node (CDLN) cells of EAU. After treating EAU with upadacitinib, we analyzed immune cell gene expression and cell–cell communication by integrating scRNA data. Additionally, we applied flow cytometry and western blot to analyze the CDLN cells.
Results
The JAK/STAT pathway was found to be upregulated in patients with VKH disease and EAU. Upadacitinib effectively alleviated EAU symptoms, reduced JAK1 protein expression, and suppressed pathogenic CD4 T cell (CD4TC) proliferation and pathogenicity while promoting Treg proliferation. The inhibition of pathogenic CD4TCs by upadacitinib was observed in both flow cytometry and scRNA data. Additionally, upadacitinib was found to rescue the interferon-stimulated gene 15 (ISG15)⁺ CD4TCs and CD8 T and B cell ratios and reduce expression of inflammatory-related genes. Upadacitinib demonstrated the ability to inhibit abnormally activated cell–cell communication, particularly the CXCR4-mediated migration pathway, which has been implicated in EAU pathogenesis. CXCR4 inhibitors showed promising therapeutic effects in EAU.
Conclusions
Our findings indicate that the JAK1-mediated signaling pathway is significantly upregulated in uveitis, and upadacitinib exhibits therapeutic efficacy against EAU. Furthermore, targeting the CXCR4-mediated migration pathway could be a promising therapeutic strategy.
Patients undergoing allogeneic hematopoietic stem cell transplantation (HSCT) are at an increased risk of developing severe acute respiratory distress syndrome (ARDS), which is characterized by peripheral bilateral patchy lung involvement. The regulatory network of RNA-binding protein (RBP)-alternative splicing (AS) in ARDS following HSCT has not been investigated. We hypothesize that RBP-AS plays a regulatory role during HSCT-ARDS. The published ARDS transcriptome data after HSCT (GSE84439) were downloaded, and the transcriptome data of 13 mRNAs were obtained by sequencing the peripheral blood of 5 HSCT-ARDS patients and 8 ARDS patients through high-throughput sequencing technology. Systematic analysis of downloaded data was performed to obtain differentially expressed RBPs, and the differentially alternative spliced pre-mRNAs in HSCT-ARDS and control groups were used to explore the global gene RBP-AS regulatory network. A total of 1769 differentially expressed genes and 4714 regulated alternative splicing events were identified in peripheral blood from HSCT-ARDS, of which 254 genes had both differential expression and differential AS. In addition, 128 RBPs were identified, of which HDGF, PCBP2, RIOK3, CISD2, and TRIM21, DDX58, MOV10 showed significantly increased or decreased expression in the HSCT-ARDS. RBPs with decreased expression had antiviral activity, while those with increased expression were involved in ROS, fibrosis, and negative viral resistance. The RBP-RASE-RASG regulatory network is constructed. It is related to the dysregulation of antiviral immunomodulation, imbalance in ROS homeostasis and pro-pulmonary fibrosis, which are involved in the development of HSCT-ARDS.
