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Combined disruption of T cell inflammatory regulators Regnase-1 and Roquin-1 enhances antitumor activity of engineered human T cells

ABSTRACT: Combined disruption of T cell inflammatory regulators Regnase-1 and Roquin-1 enhances antitumor activity of engineered human T cells

PROVIDER: PRJNA940474 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR23686966_1.fastq.gz	Fastqsanger.gz
	SRR23686966_2.fastq.gz	Fastqsanger.gz
	SRR23686967_1.fastq.gz	Fastqsanger.gz
	SRR23686967_2.fastq.gz	Fastqsanger.gz
	SRR23686968_1.fastq.gz	Fastqsanger.gz

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Combined disruption of T cell inflammatory regulators Regnase-1 and Roquin-1 enhances antitumor activity of engineered human T cells

Project description:To investigate the effect of Regnase-1 and/or Roquin-1 disruption in engineered primary human T cells, we produced CAR-T cells and TCR-T cells with single genetic disruption of Regnase-1, Roquin-1, or dual disruption of Regnase-1 and Roquin-1. We then performed differential gene expression analysis using data obtained from bulk RNA-seq of 3 different biological donors at baseline.

2023-03-15 | GSE226522 | GEO

The RNA-binding proteins Roquin-1 and Regnase-1 interact and cooperate to prevent autoimmunity

Project description:This study aimed to analyze the transcriptomic changes occuring after knockout of alleles encoding for the RNA-binding proteins Roquin-1 and Roquin-2 (DKO), Regnase-1 (KO) or a combination of all three (TKO) in Th1 cells without or after restimulation with anti-CD3/28 antibodies. Data analysis revealed that in unstimulated as well as restimulated T cells of all three knockout genotypes a number of genes is differentially expressed compared to WT cells, with the strongest deregulation seen in TKO cells. A comparison of gene expression changes of all three genotypes indicated that cooperativity of Roquin and Regnase-1 is the prevalent mode of target regulation.

2020-06-23 | GSE152961 | GEO

Combined disruption of T cell inflammatory regulators Regnase-1 and Roquin-1 enhances antitumor activity of engineered human T cells.

Project description:A fundamental limitation of T cell therapies in solid tumors is loss of inflammatory effector functions, such as cytokine production and proliferation. Here, we target a regulatory axis of T cell inflammatory responses, Regnase-1 and Roquin-1, to enhance antitumor responses in human T cells engineered with two clinical-stage immune receptors. Building on previous observations of Regnase-1 or Roquin-1 knockout in murine T cells or in human T cells for hematological malignancy models, we found that knockout of either Regnase-1 or Roquin-1 alone enhances antitumor function in solid tumor models, but that knockout of both Regnase-1 and Roquin-1 increases function further than knockout of either regulator alone. Double knockout of Regnase-1 and Roquin-1 increased resting T cell inflammatory activity and led to at least an order of magnitude greater T cell expansion and accumulation in xenograft mouse models, increased cytokine activity, and persistence. However double knockout of Regnase-1 and Roguin-1 also led to a lymphoproliferative syndrome and toxicity in some mice. These results suggest that regulators of immune inflammatory functions may be interesting targets to modulate to improve antitumor responses.

| S-EPMC10041166 | biostudies-literature

Disrupting Roquin-1 interaction with Regnase-1 induces autoimmunity and enhances antitumor responses.

Project description:Roquin and Regnase-1 proteins bind and post-transcriptionally regulate proinflammatory target messenger RNAs to maintain immune homeostasis. Either the sanroque mutation in Roquin-1 or loss of Regnase-1 cause systemic lupus erythematosus-like phenotypes. Analyzing mice with T cells that lack expression of Roquin-1, its paralog Roquin-2 and Regnase-1 proteins, we detect overlapping or unique phenotypes by comparing individual and combined inactivation. These comprised spontaneous activation, metabolic reprogramming and persistence of T cells leading to autoimmunity. Here, we define an interaction surface in Roquin-1 for binding to Regnase-1 that included the sanroque residue. Mutations in Roquin-1 impairing this interaction and cooperative regulation of targets induced T follicular helper cells, germinal center B cells and autoantibody formation. These mutations also improved the functionality of tumor-specific T cells by promoting their accumulation in the tumor and reducing expression of exhaustion markers. Our data reveal the physical interaction of Roquin-1 with Regnase-1 as a hub to control self-reactivity and effector functions in immune cell therapies.

| S-EPMC8996344 | biostudies-literature

Analysis of Roquin targetome during HCMV infection

Project description:To investigate how Roquin regulates cellular transcripts during Human cytomegalovirus (HCMV) infection, we examined the levels of cellular transcripts in cells treated control or Roquin-targeting siRNA during HCMV replication. Also, we performed Roquin crosslinking and immunoprecipitation followed by high-throughput sequencing (Roquin CLIP-seq) in HCMV-infected cells to identify which transcripts are directly bound by Roquin.

2019-08-15 | GSE132081 | GEO

The RNA-binding proteins Roquin-1 and Regnase-1 interact and cooperate to prevent autoimmunity

Project description:The RNA-binding proteins Roquin-1 and Regnase-1 interact and cooperate to prevent autoimmunity

| PRJNA641085 | ENA

Roquin promotes constitutive mRNA decay via a conserved class of stem-loop recognition motifs.

Project description:The degradation of TNFM-NM-1 mRNA is critical for restricting TNFM-NM-1 synthesis and involves a constitutive decay element (CDE) in the 3M-bM-^@M-^Y untranslated region of the mRNA. We demonstrate that the active CDE is a stem-loop RNA motif that is recognized by the RNA-binding protein Roquin. Deep sequencing of Roquin-associated mRNAs identified CDE-containing mRNAs as the primary targets of Roquin on a transcriptome-wide scale. Expression profiles of LPS treated Raw264.7 cells (input), after Roquin IP or control IP were generated by deep sequencing, in three biological replicates, using Illumina HiSeq 2000.

2013-05-15 | E-GEOD-44775 | biostudies-arrayexpress

Transcriptome analysis of LPS-stimulated BMDMs pretreated with Ctrl MO or Regnase-1-targeting MOs (Reg1-MOs)

Project description:Regnase-1 plays essential roles in restricting inflammation by acting as a RNase degrading mRNAs involved in immune reactions via the recognition of stem-loop structures in the 3’untranslated regions (UTRs). Dysregulated expression of Regnase-1 is implicated in the pathogenesis of inflammatory and autoimmune diseases in mice and humans. Here we developed a novel therapeutic strategy to suppress inflammatory responses by blocking Regnase-1 self-regulation, which was enabled by the simultaneous use of two antisense phosphorodiamidate morpholino oligonucleotides (MOs) to alter the binding affinity of Regnase-1 towards the stem-loop structures present in its 3’UTR. The Regnase-1-targeting MOs successfully stabilized Regnase-1 mRNA expression. Furthermore, increasing the abundance of Regnase-1 by MO treatment effectively reduced multiple pro-inflammatory transcripts that were controlled by Regnase-1 in BMDMs. Collectively, these data suggested that MO-mediated disruption of the Regnase-1 self-regulation pathway is an attractive therapeutic strategy to enhance Regnase-1 abundance, which could provide clinical benefits for treating inflammatory diseases through the suppression of inflammation.

2022-03-28 | GSE182641 | GEO

Effect of loss of Regnase-1 and Regnase-3 on the transcriptional profile in mouse Lin–Sca1+Kit+ (LSK) cells

Project description:Regulation of lineage biases in hematopoietic stem and progenitor cells (HSPCs) is pivotal for balanced hematopoietic output. However, little is known about the mechanism behind lineage choice in HSPCs. Here, we show that mRNA decay factors Regnase-1 (Zc3h12a) and Regnase-3 (Zc3h12c) are critical for induction of myeloid lineage priming, restricting lymphoid differentiation in HSPCs. Regnase-1- and Regnase-3-mediated control of mRNA encoding Nfkbiz, a transcriptional and epigenetic regulator, was essential for balancing lymphoid/myeloid lineage output in HSPCs in vivo. Furthermore, single cell-assay for transposase-accessible chromatin sequencing (scATAC-seq) analysis revealed that Regnase-1 and Regnase-3 control the epigenetic landscape on myeloid-related gene loci in hematopoietic stem cells (HSCs) via Nfkbiz. Consistently, an antisense oligonucleotide designed to inhibit Regnase-1- and Regnase-3-mediated Nfkbiz mRNA degradation primed HSCs toward myeloid lineages by enhancing Nfkbiz expression. Collectively, the collaboration between post-transcriptional control and chromatin remodeling by the Regnase-1/Regnase-3-Nfkbiz axis governs lineage priming, instructing HSC lineage specification.

2024-02-09 | GSE228923 | GEO

Roquin suppresses PI3K-mTOR signaling to control T cell differentiation and Treg effector function

Project description:Roquin proteins are required to preclude spontaneous T cell activation and aberrant T follicular helper (Tfh) or T helper 17 (Th17) differentiation. Here, we show that deletion of Roquin encoding alleles in regulatory T cells (Tregs) also caused the activation of conventional T cells. These Tregs exhibited a follicular Treg phenotype, CD25 downregulation and could not protect from colitis. Mechanistically, Roquin was required for full expression and activity of Pten and Foxo1, two essential signaling molecules in Tregs and effector T cells. Roquin upregulated Pten by interfering with miR-17~92 binding to an overlapping cis-element in the Pten 3' UTR and downregulated the Foxo1-specific E3 ubiquitin ligase Itch. Loss of Roquin enhanced mTOR signaling and global protein synthesis, while inhibition of PI3K or mTOR in Roquin-deficient CD4+ T cells corrected increased Tfh and Th17 differentiation. Thereby, the control of PI3K-mTOR signaling by Roquin prevents autoimmunity through T cell-intrinsic and Treg-mediated regulation.

2018-01-08 | GSE86110 | GEO

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