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Structural Basis for the Interaction of 14-3-3<i>β</i>with Tricarboxylic Acid Cycle Intermediate Malate

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Journal of Biosciences and Medicines 2017年第8期5卷 36-47页

作者： Zhiqiang Hou Lijing Su Xiaoyan Liu Department of Biophysics Dallas USA center for Alzheimer and Neurodegenerative Disease Dallas USA center for the genetics of host defense Dallas USA Department of Microbiology University of Texas Southwestern Medical Center Dallas USA

The protein family of 14-3-3(s) has risen to a position of higher importance as an adaptor protein in cell biology. The seven highly conserved human 14-3-3 proteins coordinate diverse cellular processes including apoptosis, DNA damage response, protein trafficking, and others. In liver hepatocytes, 14-3-3β binds to Ser196-phosphorilated glucose-responsive carbohydrate response element-binding protein (ChREBP) to inhibit converting excess carbohydrate to fat by regulating the nuclear/cytosol trafficking of ChREBP. Here, we report X-ray crystal structures of homodimeric mammalian 14-3-3β in its apo, Malate-bound forms. The determined apo structure was captured with one monomer in the closed state, whereas the other one had an open conformation. Strikingly, 14-3-3β binds Malate dynamically with a double-closed state, which is distinct from all previously characterized 14-3-3(s) and target ligand-binding modes. Malate docks into a first-time observed cofactor pocket located at the concaved interface of 14-3-3β helices α2, α3, α4 through mainly electrostatic and hydrogen interactions. Such a Tricarboxylic Acid Cycle intermediate Malate bond model might offer a new approach to further analyze insulin-independent 14-3-3/ChREBP pathway of de novo fat synthesis in the liver.

关键词： Crystal Structure 14-3-3 Protein ChREBP Transcription Activation Malate Malic Acid

Expression of the human TSPY gene in the brains of transgenic mice suggests a potential role of this Y chromosome gene in neural functions

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Journal of genetics and Genomics 2011年第5期38卷 181-191页

作者： Tatsuo Kido Stephanie Schubert Jrg Schmidtke Yun-Fai Chris Lau Division of Cell and Developmental genetics Department of MedicineVA Medical Centerand Institute for Human GeneticsUniversity of California Institute of Human genetics Hannover Medical School

The testis specific protein Y-encoded （TSPY） is a member of TSPY/SET/NAP1 superfamily, encoded within the gonadoblastoma locus on the Y chromosome. TSPY shares a highly conserved SET/NAP-domain responsible for protein--protein interaction among TSPY/SET/NAP 1 proteins. Accumulating data, so far, support the role of TSPYas the gonadoblastoma gene, involved in germ cell tumorigenesis. The X-chromosome homolog of TSPY, TSPX is expressed in various tissues at both fetal and adult stages, including the brain, and is capable of interacting with the multi-domain adapter protein CASK, thereby influencing the synaptic and transcriptional functions and developmental regulation of CASK in the brain and other neural tissues. Similar to TSPX, we demonstrated that TSPY could interact with CASK at its SET/NAP-domain in cultured cells. Transgenic mice harboring a human TSPYgene and flanking sequences showed specific expression of the human TSPYtransgene in both testis and brain. The neural expression pattern of the human TSPYgene overlapped with those of the endogenous mouse Cask and Tspx gene. Similarly with TSPX, TSPY was co-localized with CASK in neuronal axon fibers in the brain, suggesting a potential role（s） of TSPY in development and/or physiology of the nervous system.

关键词： TSPY TSPX CASK Y chromosome Neuron Testis

Identification of a TSPY co-expression network associated with DNA hypomethylation and tumor gene expression in somatic cancers

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Journal of genetics and Genomics 2016年第10期43卷 577-585页

作者： Tatsuo Kido Yun-Fai Chris Lau Division of Cell and Developmental genetics Department of Medicine Veterans Affairs Medical Center and Institute for Human Genetics University of California

Testis specific protein Y-encoded（TSPY） is a Y-located proto-oncogene predominantly expressed in normal male germ cells and various types of germ cell tumor. Significantly, TSPY is frequently expressed in somatic cancers including liver cancer but not in adjacent normal tissues, suggesting that ectopic TSPY expression could be associated with oncogenesis in non-germ cell cancers. Various studies demonstrated that TSPY expression promotes growth and proliferation in cancer cells; however, its relationship to other oncogenic events in TSPY-positive cancers remains unknown. The present study seeks to correlate TSPY expression with other molecular features in clinical cancer samples, by analyses of RNA-seq transcriptome and DNA methylation data in the Cancer Genome Atlas（TCGA） database. A total of 53 genes,including oncogenic lineage protein 28 homolog B（LIN28B） gene and RNA-binding motif protein Y-linked（RBMY） gene, are identified to be consistently co-expressed with TSPY, and have been collectively designated as the TSPY co-expression network（TCN）. TCN genes were simultaneously activated in subsets of liver hepatocellular carcinoma（30%） and lung adenocarcinoma（10%） regardless of pathological stage, but only minimally in other cancer types. Further analysis revealed that the DNA methylation level was globally lower in the TCN-active than TCN-silent cancers. The specific expression and methylation patterns of TCN genes suggest that they could be useful as biomarkers for the diagnosis,prognosis and clinical management of cancers, especially those for liver and lung cancers, associated with TSPY co-expression network genes.

关键词： Co-expression network DNA methylation Gene expression signature Cancer subclassification Y chromosome genes TSPY Cancer/testis antigens

Emerging roles of spliceosome in cancer and immunity

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Protein & Cell 2022年第8期13卷 559-579页

作者： Hui Yang Bruce Beutler Duanwu Zhang Department of Neurosurgery Huashan HospitalShanghai Key laboratory of Brain Function Restoration and Neural RegenerationMOE Frontiers Center for Brain ScienceInstitute for Translational Brain ResearchShanghai Medical CollegeFudan UniversityShanghai 200032China center for the genetics of host defense University of Texas Southwestern Medical CenterDallasTX 75390USA Children's Hospital of Fudan University and Shanghai Key Laboratory of Medical EpigeneticsInternational Co-laboratory of Medical Epigenetics and MetabolismMinistry of Science and TechnologyInstitutes of Biomedical SciencesFudan UniversityShanghai 200032China

Precursor messenger RNA(pre-mRNA)splicing is cat-alyzed by an intricate ribonucleoprotein complex called the *** the spliceosome is consid-ered to be general cell"housekeeping"machinery,mutations in core components of the spliceosome fre-quently correlate with cell-or tissue-specific pheno-types and *** this review,we expound the links between spliceosome mutations,aberrant splicing,and human ***,spliceosome-targeted therapios(STTs)have become efficient anti-cancer strategies for cancer patients with splicing *** also highlight the links between spliceosome and immune *** studies have shown that some spliceosome gene mutations can result in immune dysregulation and notable phenotypes due to mis-splicing of immune-related ***,several core spliceosome components harbor splicing-inde-pendent immune functions within the cell,expanding the functional repertoire of these diverse proteins.

关键词： spliceosome splicing cancer innate immunity immune dysregulation

Growth phase dependent changes in the structure and protein composition of nucleoid in Escherichia coli

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Science China(Life Sciences) 2015年第9期58卷 902-911页

作者： TALUKDER AliAzam ISHIHAMA Akira Department of Microbiology Jahangirnagar University Micro-Nano Technology Research center Hosei University Department of Molecular genetics National Institute of Genetics

The genomic DNA of bacteria is highly compacted in a single or a few bodies known as nucleoids. Here, we have isolated Escherichia coli nucleoid by sucrose density gradient centrifugation. The sedimentation rates, structures as well as pro- tein/DNA composition of isolated nucleoids were then compared under various growth phases. The nucleoid structures were found to undergo changes during the cell growth; i. e., the nucleoid structure in the stationary phase was more tightly com- pacted than that in the exponential phase. In addition to factor for inversion stimulation （Fis）, histone-like nucleoid structuring protein （H-NS）, heat-unstable nucleoid protein （HU） and integration host factor （IHF） here we have identified, three new can- didates of E. coli nucleoid, namely DNA-binding protein from starved cells （Dps）, host factor for phage QJ3 （Hfq） and sup- pressor of taC phenotype A （StpA）. Our results reveal that the major components of exponential phase nucleoid are Fis, HU, H-NS, StpA and Hfq, while Dps occupies more than half of the stationary phase nucleoid. It has been known for a while that Dps is the main nucleoid-associated protein at stationary phase. From these results and the prevailing information, we propose a model for growth phase dependent changes in the structure and protein composition of nucleoid in E. coli.

关键词： growth phase sucrose gradient bacterial nucleoid DNA binding protein DNA compaction

Invariant natural killer T cells and iron metabolism orchestrate skin development and homeostasis

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Cellular & Molecular Immunology 2023年第10期20卷 1095-1097页

作者： Hiroshi Nabeshima Takayuki Niitsu Kiyoharu Fukushima Hiroshi Kida Laboratory of host defense World Premier Institute Immunology Frontier Research Center(WPI-IFReC)Osaka University3-1 YamadaokaSuitaOsakaJapan Department of Respiratory Medicine and Clinical Immunology Osaka University Graduate School of Medicine2-2 YamadaokaSuitaOsakaJapan Department of host defense Research Institute for Microbial Diseases(RIMD)Osaka University3-1 YamadaokaSuitaOsakaJapan Department of Respiratory Medicine National Hospital Organization Osaka Toneyama Medical Center5-1-1 ToneyamaOsakaJapan Global center for Medical Engineering and Informatics 2-2 YamadaokaSuitaOsakaJapan

In recent years,innate-like T-cell populations,such as invariant natural killer T(iNKT)cells and mucosal-associated invariant T(MAIT)cells,have been identified[1].These cells are different from conventional T cells in that they reside in tissues such as the liver,lung,and skin,rather than the lymph node and spleen[2].Although iNKT and MAIT cells are abundant in the skin immediately after birth,the detailed functions or the mechanisms regulating their localization have not been clarified[3].In a study published in Nature Immunology,Wang et *** that the early homing of iNKT cells to the skin was dependent on CCR10 expression during the stage of thymic development and was critical for proper commensal bacterial colonization and skin development[4].

关键词： killer metabolism homeostasis

Specific targeting of lung ILC2s via NRP1 in pulmonary fibrosis

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Cellular & Molecular Immunology 2022年第8期19卷 869-871页

作者： Takuro Nii Kiyoharu Fukushima Hiroshi Kida Department of Respiratory Medicine National Hospital Organization Osaka Toneyama Medical Center5-1-1 ToneyamaOsakaJapan Department of Respiratory Medicine and Clinical Immunology Osaka University Graduate School of Medicine2-2 YamadaokaSuitaOsakaJapan Laboratory of host defense World Premier Institute Immunology Frontier Research Center(WPI-IFReC)Osaka University3-1 YamadaokaSuitaOsakaJapan Department of host defense Research Institute for Microbial Diseases(RIMD)Osaka UniversityOsaka565-0871Japan Global center for Medical Engineering and Informatics 2-2 YamadaokaSuitaOsakaJapan

Innate lymphoid cells are predominantly tissue-resident immune cells that have diverse functions similar to T-cell subsets and regulate tissue homeostasis and innate immunity without specific antigen recognition. Prev... 详细信息

关键词： ILC2s immunity homeostasis

Battle of the sexes: contrasting roles of testis-specific protein Y-encoded (TSPY) and TSPX in human oncogenesis

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Asian Journal of Andrology 2019年第3期21卷 260-269页

作者： Yun-Fai Chris Lau Yunmin Li Tatsuo Kido Division of Cell and Developmental genetics Department of Medicine VA Medical Center and Institute for Human Genetics University of California San Francisco CA 94121 USA

The Y-located testis-specific protein Y-encoded (TSPY) and its X-homologue TSPX originated from the same ancestral gene, but act as a proto-oncogene and a tumor suppressor gene, respectively. TSPY has specialized in male-specific functions, while TSPX has assumed the functions of the ancestral gene. Both TSPY and TSPX harbor a conserved SET/NAP domain, but are divergent at flanking structures. Specifically, TSPX contains a C-terminal acidic domain, absent in TSPY. They possess contrasting properties, in which TSPY and TSPX, respectively, accelerate and arrest cell proliferation, stimulate and inhibit cyclin B-CDK1 phosphorylation activities, have no effect and promote proteosomal degradation of the viral HBx oncoprotein, and exacerbate and repress androgen receptor (AR) and constitutively active AR variant, such as AR-V7, gene transactivation. The inhibitory domain has been mapped to the carboxyl acidic domain in TSPX, truncation of which results in an abbreviated TSPX exerting positive actions as TSPY. Transposition of the acidic domain to the C-terminus of TSPY results in an inhibitory protein as intact TSPX. Hence, genomic mutations/aberrant splicing events could generate TSPX proteins with truncated acidic domain and oncogenic properties as those for TSPY. Further, TSPY is upregulated by AR and AR-V7 in ligand-dependent and ligand-independent manners, respectively, suggesting the existence of a positive feedback loop between a Y-located proto-oncogene and male sex hormone/receptors, thereby amplifying the respective male oncogenic actions in human cancers and diseases. TSPX counteracts such positive feedback loop. Hence, TSPY and TSPX are homologues on the sex chromosomes that function at the two extremes of the human oncogenic spectrum.

关键词： androgen receptor AR-V7 cell cycle regulation cyclin B-CDK1 oncogene sex chromosomes sex differences TSPX TSPY tumor suppressor

Long noncoding RNA: TRIMming the viral load

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Cellular & Molecular Immunology 2019年第11期16卷 843-845页

作者： Akhilesh Kumar Himanshu Kumar Laboratory of Immunology and Infectious Disease Biology Department of Biological SciencesIndian Institute of Science Education and Research BhopalBhopal By-pass roadBhauriBhopalMadhya Pradesh 462066India Laboratory of host defense WPI Immunology Frontier Research CenterOsaka University3-1 Yamada-okaSuitaOsaka 565-0871Japan

Viruses are obligate intracellular entities that require a living host and its machinery for *** replication,viral components known as pathogen-associated molecular patterns(PAMPs)are sensed by a family of innate immune sensors or pattern recognition receptors(PRRs)and promote an antiviral *** nucleic acids are one of the key PAMPs sensed by cytosolic RIG-I-like receptors(RLRs),Cyclic GMP-AMP Synthase(cGAS),Absent In Melanoma 2(AIM2),Interferon Gamma Inducible Protein 16(IFI16),and Z-DNA Binding Protein 1(ZBP1 or DAI)and endosome-localized Toll-like receptors(TLR3,7,8,and 9).1 Recognition of viral RNA by Retinoic acid-inducible gene I(RIG-I),Melanoma differentiation associated gene 5(MDA5),and TLR3,7,and 8 or viral DNA by TLR9,cGAS,AIM2,IFI16,and DAI triggers a cascade of signaling events to recruit transcription factors,interferon regulatory factors and NF-κ*** IRF3/7 and NF-κB translocate to the nucleus and induce expression of type I and III interferons and proinflammatory cytokines,respectively.1 The production of these interferons is further enhanced in an autocrine and paracrine manner through the JAK-STAT signaling *** I and III interferons further induce interferoninducible genes,and together with proinflammatory cytokines,they develop an antiviral *** antiviral state is characterized by by apoptosis of virally infected cells and inhibition of the cellular protein synthesis machinery,making the uninfected cells resistant to viral infection and initiates virus-specific adaptive immune responses(Fig.1a).

关键词： interferon load viral