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Leucine zipper-based sorting system enables generation of multi-functional CAR T cells

ABSTRACT: Leucine zipper-based sorting system enables generation of multi-functional CAR T cells

PROVIDER: PRJNA1066293 | ENA |

REPOSITORIES: ENA

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Leucine zipper-based sorting system enables generation of multi-functional CAR T cells

Project description:Resistance to chimeric antigen receptor (CAR) T cell therapy develops through multiple mechanisms including antigen-loss escape and tumor-induced immune suppression. Expression of multiple CARs may overcome multi-antigen-loss escape. Similarly, expression of switch receptors that convert inhibitory immune checkpoint signals into positive costimulatory signals may enhance CAR T cell activity in the tumor microenvironment. Engineering multiple features into one cell product, however, is limited by transgene packaging constraints of current vector systems. Here, we describe a leucine zipper-based cell sorting methodology that enables selective single-step immunomagnetic purification of cells co-transduced with two vectors, designed to potentially double the number of incorporated transgenes. This “Zip-sorting” system facilitated generation of T cells simultaneously expressing up to four CARs and co-expressing up to three switch receptors. These multi-CAR multi-Switch receptor arrays enabled T cells to eliminate antigenically heterogeneous syngeneic leukemia populations co-expressing multiple inhibitory ligands. Zip-sorted multi-CAR multi-Switch receptor T cells represent a combinatorial therapeutic strategy to overcome multiple mechanisms of CAR T cell resistance.

2024-11-24 | GSE253563 | GEO

Project description:Leucine zipper-based sorting system enables generation of multi-functional CAR T cells

| PRJNA1052637 | ENA

Intricate coupling between the transactivation and basic-leucine zipper domains governs the CK2-dependent phosphorylation of ATF4

Project description:Most transcription factors possess at least one long intrinsically disordered transactivation domain that binds to a variety of co-activators and co-repressors and plays a key role in modulating the transcriptional activity. Despite the crucial importance of these mechanisms, the structural and functional basis of transactivation domain in yet poorly understood. Here, we focused on ATF4/CREB-2, an essential transcription factor for cellular stress adaptation. We found that the N-terminal region of the transactivation domain is involved in transient long-range interactions with the basic-leucine zipper domain. In vitro phosphorylation assays with the protein kinase CK2 show that the presence of the basic-leucine zipper domain is required for optimal phosphorylation of the transactivation domain. This study uncovers the intricate coupling existing between the transactivation and basic-leucine zipper domains of ATF4 and highlights its potential functional relevance.

2023-03-11 | PXD029704 | Pride

Deep mutational scanning of the interaction of JUN's leucine zipper domain and other human bZIPs in different experimental conditions

Project description:Deep mutational scanning of the interaction of JUN's leucine zipper domain and other human bZIPs in different experimental conditions

2023-10-18 | GSE245485 | GEO

Immunomodulatory effects of glucocorticoid-induced leucine zipper (GILZ) expression in murine bone-marrow derived macrophages.

Project description:Here, we provide evidence for the immunomodulatory effects of glucocorticoid-induced leucine zipper (GILZ) overexpression in macrophages, demonstrating enhanced antibacterial activity, protection from pyroptosis, and altered mitochondrial function. Additionally, our findings reveal a significant impact on MMP activity, suggesting a role for GILZ in influencing extracellular matrix remodeling and wound healing processes. The study contributes to explorations of GILZ in its significance in pro-resolving macrophage functions.

2024-05-13 | GSE254137 | GEO

Identification of Glucocorticoid-Induced Leucine Zipper (Gilz) gene targets in undifferentiated spermatogonia

Project description:Identification of Glucocorticoid-Induced Leucine Zipper (Gilz) gene targets in undifferentiated spermatogonia

| PRJNA421886 | ENA

INK4A expression in leukemic cells transformed by the v-Myb oncoprotein depends on the integrity of the v-Myb leucine zipper region

Project description:The AMV v-Myb oncoprotein causes oncogenic transformation of myelomonocytic cells in vivo and in vitro. Its transforming capacity is strictly dependent upon the N-terminal DNA binding domain, the central transactivation region, and on the C-terminal domain containing a putative leucine zipper motif. While deletions in the central part of the leucine zipper region or point mutations of critical leucine residues abolish the leukemogenicity of the protein, a small deletion within the N-terminal part (deltaP mutant) preserves almost full in vitro transforming ability and only weakens the leukemogenic potential in vivo. We analyzed the gene expression profiles of ex vivo cultures transformed with either wild type or deltaP mutant of v-Myb. A few tens of genes were found to be significantly and reproducibly differentially expressed between the two cultures. Among them, the transcript of the CDKN2A gene, which is critically involved in the cell cycle progression regulation, showed higher expression in the deltaP mutant transformed cells. In mammals and also some avian species, there are two different mRNAs - ARF and INK4A – transcribed from the CDKN2A locus. It is known that in chickens the locus had been rearranged in evolution and only one mRNA is transcribed. We found that this mRNA encodes both ARF and INK4A and that the INK4A protein translation starts with a GUG codon downstream of the ARF AUG initiation codon and proceeds in a different reading frame. INK4A protein thus exists in chicken cells as well and its negative regulation by v-Myb is a part of the leukemic transformation mechanism. Comparison of expression profiles of chicken monoblasts transformed either by wild type v-myb or its mutated version designated deltaP. Three biological replicates were analyzed for each group.

2012-04-11 | E-GEOD-35413 | biostudies-arrayexpress

INK4A expression in leukemic cells transformed by the v-Myb oncoprotein depends on the integrity of the v-Myb leucine zipper region

2012-04-12 | GSE35413 | GEO

Immunomodulatory effects of glucocorticoid-induced leucine zipper (GILZ) expression in murine bone-marrow derived macrophages.

Project description:Immunomodulatory effects of glucocorticoid-induced leucine zipper (GILZ) expression in murine bone-marrow derived macrophages.

| PRJNA1068618 | ENA

The Cytoskeletal Stress Response Pathway: a homeostatic system driven by Dual Leucine Zipper Kinase (DLK)

Project description:The Cytoskeletal Stress Response Pathway: a homeostatic system driven by Dual Leucine Zipper Kinase (DLK)

| PRJNA1025272 | ENA