Jesus Izaguirre-Carbonell

IR Dynamics (United States)

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Fumio Sugawara

Tokyo University of Science

Shinji Kamisuki

Azabu University

Nan Zhu

Versiti Blood Center of Wisconsin

Senko Tsukuda

University of Oxford

Tomoe Kusayanagi

Tokyo University of Science

Luke Christiansen

Medical College of Wisconsin

Demin Wang

Versiti Blood Center of Wisconsin

Theresa Bluemn

Medical College of Wisconsin

Yongwei Zheng

Vision Medicals (China)

Yoshihiro Kanai

Dai Nippon Printing (Japan)

Cooperative Institutions

Tokyo University of Science

Versiti Blood Center of Wisconsin

The University of Tokyo

Kurume University

National Institute of Infectious Diseases

Medical College of Wisconsin

National Institutes of Health

London Health Sciences Centre

Western University

Keio University

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Mapping a Disordered Portion of the Brz2001-Binding Site on a Plant Monooxygenase, DWARF4, Using a Quartz-Crystal Microbalance Biosensor-Based T7 Phage Display

Assay and Drug Development Technologies (2013)

Yoichi Takakusagi Daisuke Manita Tomoe Kusayanagi Jesus Izaguirre-Carbonell Kaori Takakusagi

In small-molecule/protein interaction studies, technical difficulties such as low solubility of small molecules or low abundance of protein samples often restrict the progress of research. Here, we describe a quartz-crystal microbalance (QCM) biosensor-based T7 phage display in combination use with a receptor-ligand contacts (RELIC) bioinformatics server for application in a plant Brz2001/DWARF4 system. Brz2001 is a brassinosteroid biosynthesis inhibitor in the less-soluble triazole series of compounds that targets DWARF4, a cytochrome P450 (Cyp450) monooxygenase containing heme and iron. Using a Brz2001 derivative that has higher solubility in 70% EtOH and forms a self-assembled monolayer on gold electrode, we selected 34 Brz2001-recognizing peptides from a 15-mer T7 phage-displayed random peptide library using a total of four sets of one-cycle biopanning. The RELIC/MOTIF program revealed continuous and discontinuous short motifs conserved within the 34 Brz2001-selected 15-mer peptide sequences, indicating the increase of information content for Brz2001 recognition. Furthermore, an analysis of similarity between the 34 peptides and the amino-acid sequence of DWARF4 using the RELIC/MATCH program generated a similarity plot and a cluster diagram of the amino-acid sequence. Both of these data highlighted an internally located disordered portion of a catalytic site on DWARF4, indicating that this portion is essential for Brz2001 recognition. A similar trend was also noted by an analysis using another 26 Brz2001-selected peptides, and not observed using the 27 gold electrode-recognizing control peptides, demonstrating the reproducibility and specificity of this method. Thus, this affinity-based strategy enables high-throughput detection of the small-molecule-recognizing portion on the target protein, which overcomes technical difficulties such as sample solubility or preparation that occur when conventional methods are used.

Biopanning

Quartz Crystal Microbalance

10.1089/adt.2012.478

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Citations (9)

Fungus-Derived Neoechinulin B as a Novel Antagonist of Liver X Receptor, Identified by Chemical Genetics Using a Hepatitis C Virus Cell Culture System

Journal of Virology (2016)

Syo Nakajima Koichi Watashi Hirofumi Ohashi Shinji Kamisuki Jesus Izaguirre-Carbonell

ABSTRACT Cell culture systems reproducing virus replication can serve as unique models for the discovery of novel bioactive molecules. Here, using a hepatitis C virus (HCV) cell culture system, we identified neoechinulin B (NeoB), a fungus-derived compound, as an inhibitor of the liver X receptor (LXR). NeoB was initially identified by chemical screening as a compound that impeded the production of infectious HCV. Genome-wide transcriptome analysis and reporter assays revealed that NeoB specifically inhibits LXR-mediated transcription. NeoB was also shown to interact directly with LXRs. Analysis of structural analogs suggested that the molecular interaction of NeoB with LXR correlated with the capacity to inactivate LXR-mediated transcription and to modulate lipid metabolism in hepatocytes. Our data strongly suggested that NeoB is a novel LXR antagonist. Analysis using NeoB as a bioprobe revealed that LXRs support HCV replication: LXR inactivation resulted in dispersion of double-membrane vesicles, putative viral replication sites. Indeed, cells treated with NeoB showed decreased replicative permissiveness for poliovirus, which also replicates in double-membrane vesicles, but not for dengue virus, which replicates via a distinct membrane compartment. Together, our data suggest that LXR-mediated transcription regulates the formation of virus-associated membrane compartments. Significantly, inhibition of LXRs by NeoB enhanced the activity of all known classes of anti-HCV agents, and NeoB showed especially strong synergy when combined with interferon or an HCV NS5A inhibitor. Thus, our chemical genetics analysis demonstrates the utility of the HCV cell culture system for identifying novel bioactive molecules and characterizing the virus-host interaction machinery. IMPORTANCE Hepatitis C virus (HCV) is highly dependent on host factors for efficient replication. In the present study, we used an HCV cell culture system to screen an uncharacterized chemical library. Our results identified neoechinulin B (NeoB) as a novel inhibitor of the liver X receptor (LXR). NeoB inhibited the induction of LXR-regulated genes and altered lipid metabolism. Intriguingly, our results indicated that LXRs are critical to the process of HCV replication: LXR inactivation by NeoB disrupted double-membrane vesicles, putative sites of viral replication. Moreover, NeoB augmented the antiviral activity of all known classes of currently approved anti-HCV agents without increasing cytotoxicity. Thus, our strategy directly links the identification of novel bioactive compounds to basic virology and the development of new antiviral agents.

10.1128/jvi.00856-16

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Critical role of Jumonji domain of JMJD1C in MLL-rearranged leukemia

Blood Advances (2019)

Jesus Izaguirre-Carbonell Luke Christiansen Robert Burns Jesse Schmitz Chenxuan Li

JMJD1C, a member of the lysine demethylase 3 family, is aberrantly expressed in mixed lineage leukemia (MLL) gene-rearranged (MLLr) leukemias. We have shown previously that JMJD1C is required for self-renewal of acute myeloid leukemia (AML) leukemia stem cells (LSCs) but not normal hematopoietic stem cells. However, the domains within JMJD1C that promote LSC self-renewal are unknown. Here, we used clustered regularly interspaced short palindromic repeats (CRISPR)/CRISPR-associated protein-9 nuclease (Cas9) negative-selection screening and identified a requirement for the catalytic Jumonji (JmjC) domain and zinc finger domain for leukemia cell survival in vitro and in vivo. In addition, we found that histone H3 lysine 36 methylation (H3K36me) is a marker for JMJD1C activity at gene loci. Moreover, we performed single cell transcriptome analysis of mouse leukemia cells harboring a single guide RNA (sgRNA) against the JmjC domain and identified increased activation of RAS/MAPK and the JAK-STAT pathway in cells harboring the JmjC sgRNA. We discovered that upregulation of interleukin 3 (IL-3) receptor genes mediates increased activation of IL-3 signaling upon JMJD1C loss or mutation. Along these lines, we observed resistance to JMJD1C loss in MLLr AML bearing activating RAS mutations, suggesting that RAS pathway activation confers resistance to JMJD1C loss. Overall, we discovered the functional importance of the JMJD1C JmjC domain in AML leukemogenesis and a novel interplay between JMJD1C and the IL-3 signaling pathway as a potential resistance mechanism to targeting JMJD1C catalytic activity.

Demethylase

10.1182/bloodadvances.2018026054

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Citations (24)

Differential roles of BAF and PBAF subunits, Arid1b and Arid2, in MLL-AF9 leukemogenesis

Leukemia (2022)

Theresa Bluemn Jesse Schmitz Yongwei Zheng Robert Burns Shikan Zheng

SWI/SNF

SMARCA4

10.1038/s41375-021-01505-w

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Identification of SQAP-Binding Proteins from a T7 Phage Display Screen

Planta Medica (2013)

Jesus Izaguirre-Carbonell Hisashi Murata Keisuke Ohta Tomoe Kusayanagi Senko Tsukuda

Sulfoquynovosylacylpropanediol (SQAP, below figure) was chemically designed from SQMG isolated from sea urchins as a result of natural products research. SQAP performed synergistically inhibition of angiogenesis at low doses in a combination therapy with ionizing radiation. Four SQAP-binding candidate proteins were identified by a T7 phage display screen as follows: sterol carrier protein 2 (SCP-2), multifunctional enzyme type 2 (MFE-2), proteasomal ubiquitin receptor (ADRM1) and UV excision repair protein (HR23B). Two independent experiments were used to verify the interactions between SQAP and the observed candidate peptides. In a parallel research, downregulation of histone deacetylase 1 (HDAC1) was also observed under SQAP treatment.

Target protein

HDAC1

10.1055/s-0033-1348586

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Critical Role of Jumonji Domain of JMJD1C in AML Leukemogenesis

Blood (2018)

Jesus Izaguirre-Carbonell Luke Christiansen Robert Burns Jesse Schmitz Chenxuan Li

10.1182/blood-2018-99-110463

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Detection of Circulating Tumor DNA After Stereotactic Ablative Radiotherapy in Patients With Unbiopsied Lung Tumors (SABR-DETECT)

Clinical Lung Cancer (2023)

Saurav Verma Sympascho Young Thomas Kennedy Ilda Carvalhana Morgan Black

Ablative case

Liquid biopsy

10.1016/j.cllc.2023.11.013

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Citations (1)

Arid2 regulates hematopoietic stem cell differentiation in normal hematopoiesis

Experimental Hematology (2020)

Theresa Bluemn Jesse Schmitz Yuhong Chen Yongwei Zheng Yongguang Zhang

The switch/sugar nonfermenting (SWI/SNF) family of chromatin remodeling complexes have been implicated in normal hematopoiesis. The ARID2 protein is a component of the polybromo-associated BAF (PBAF), one of the two main SWI/SNF complexes. In the current study, we used a conditional Arid2 knockout mouse model to determine its role in normal hematopoiesis. We found that the loss of Arid2 has no discernable effects on steady-state hematopoiesis, with the exception of a modest effect on erythropoiesis. On bone marrow transplantation, however, the loss of Arid2 affects HSC differentiation in a cell-autonomous manner, resulting in significant decreases in the ability to reconstitute the lymphoid lineage. Gene expression analysis of Arid2 knockout cells revealed enrichment of myeloid-biased multipotent progenitor (MPP) cell signatures, while the lymphoid-biased MPPs are enriched in the wild type, consistent with the observed phenotype. Moreover, Arid2 knockout cells revealed enrichment of inflammatory pathways with upregulation of TLR receptors, as well as downstream signaling cascade genes. Furthermore, under lymphocyte-biased growth conditions in vitro, Arid2 null bone marrow cells have significantly impaired proliferation, which decreased further on lipopolysaccharide stimulation. Overall, these data suggest that the loss of Arid2 impairs HSC differentiation ability, and this effect may be mediated through upregulation of inflammatory pathways.

Hematopoietic stem cell

10.1016/j.exphem.2020.12.004

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Citations (12)

JMJD1C Interacts with the Ncor Corepressor Complex and Is Required for Human MLL-AF9 Leukemogenesis

Blood (2022)

Olivia Arnold Luke Christiansen Jesus Izaguirre-Carbonell Theresa Bluemn Mark Wunderlich

10.1182/blood-2022-166806

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Identification and study of SQAP-binding proteins from a T7 phage display screen

Planta Medica (2014)

Jesus Izaguirre-Carbonell Hisashi Murata Keisuke Ohta Tomoe Kusayanagi Senko Tsukuda

Sulfoquynovosylacylpropanediol (SQAP) was chemically designed from SQMG isolated from sea urchins as a result of natural products research. SQAP performed synergistically inhibition of angiogenesis at low doses in a combination therapy with ionizing radiation. However, the radiobiological mechanisms of SQAP remain unknown. We performed a T7 phage display screen in order to identify SQAP binding proteins. We could identify five SQAP-binding proteins including Focal Adhesion Kinase (FAK). Two independent experiments were used to verify the interactions. We observed that SQAP can modulate FAK phosphorylation induced by VEGF. Additionally, downregulation of HDAC1 has been observed under SQAP treatment. Therefore, we have investigated histone acetylation level and observed an upregulated acetylation induced by SQAP.

10.1055/s-0034-1382611

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Citations (1)