Details of a Researcher - Yoshikawa, Harunori

Papers - Yoshikawa, Harunori

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Linear ubiquitination triggers Amph-mediated T-tubule biogenesis

Kohei Kawaguchi, Yutaro Hama, Harunori Yoshikawa, Kohei Nishino, Kazuki Morimoto, Tsuyoshi Nakamura, Michiko Koizumi, Yuriko Sakamaki, Kota Abe, Soichiro Kakuta, Koichiro Ichimura, Fumiyo Ikeda, Hidetaka Kosako, Naonobu Fujita

2025.04

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Cover Feature: Sulfoxide‐Mediated Cys‐Trp‐Selective Bioconjugation that Enables Protein Labeling and Peptide Heterodimerization (ChemistryEurope 3‐4/2024)

Daishiro Kobayashi, Masaya Denda, Junya Hayashi, Kota Hidaka, Yutaka Kohmura, Takaaki Tsunematsu, Kohei Nishino, Harunori Yoshikawa, Kento Ohkawachi, Kiyomi Nigorikawa, Tetsuro Yoshimaru, Naozumi Ishimaru, Wataru Nomura, Toyomasa Katagiri, Hidetaka Kosako, Akira Otaka

ChemistryEurope 2024.05

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Proteomic and functional comparison between human induced and embryonic stem cells

Alejandro J. Brenes, Eva Griesser, Linda V. Sinclair, Lindsay Davidson, Alan R. Prescott, Francois Singh, Elizabeth K.J. Hogg, Carmen Espejo-Serrano, Hao Jiang, Harunori Yoshikawa, Melpomeni Platani, Jason Swedlow, Greg M. Findlay, Doreen A. Cantrell, Angus I. Lamond

eLife (eLife Sciences Publications, Ltd) 2024.02

Human induced pluripotent stem cells (hiPSCs) have great potential to be used as alternatives to embryonic stem cells (hESCs) in regenerative medicine and disease modelling, thereby avoiding ethical issues arising from the use of embryo-derived cells. However, despite clear similarities between the two cell types, it is likely they are not identical. In this study we characterise the proteomes of multiple hiPSC and hESC lines derived from independent donors. We find that while hESCs and hiPSCs express a near identical set of proteins, they show consistent quantitative differences in the expression levels of a wide subset of proteins. hiPSCs have increased total protein content, while maintaining a comparable cell cycle profile to hESCs. The proteomic data show hiPSCs have significantly increased abundance of vital cytoplasmic and mitochondrial proteins required to sustain high growth rates, including nutrient transporters and metabolic proteins, which correlated with phenotypic differences between hiPSCs and hESCs. Thus, higher levels of glutamine transporters correlated with increased glutamine uptake, while higher levels of proteins involved in lipid synthesis correlated with increased lipid droplet formation. Some of the biggest metabolic changes were seen in proteins involved in mitochondrial metabolism, with corresponding enhanced mitochondrial potential, shown experimentally using high-resolution respirometry. hiPSCs also produced higher levels of secreted proteins including ECM components and growth factors, some with known tumorigenic properties as well as proteins involved in the inhibition of the immune system. Our data indicate that reprogramming of human fibroblasts to iPSCs effectively restores protein expression in cell nuclei to a similar state to hESCs, but does not similarly restore the profile of cytoplasmic and mitochondrial proteins, with consequences for cell phenotypes affecting growth and metabolism. The data improve understanding of the molecular differences between induced and embryonic stem cells with implications for potential risks and benefits for their use in future disease modelling and therapeutic applications.

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がん特殊化リボソームの同定と機能解析(Identification and characterization of cancer-specialized ribosomes)

常松貴明, 吉川治孝, 永尾瑠佳, 松澤鎮史, 大塚邦紘, 牛尾綾, 石丸直澄

日本病理学会会誌 ((一社)日本病理学会) 113 ( 1 ) 295 - 295 2024.02

ISSN 0300-9181

An allele-selective inter-chromosomal protein bridge supports monogenic antigen expression in the African trypanosome

Joana R. C. Faria, Michele Tinti, Catarina A. Marques, Martin Zoltner, Harunori Yoshikawa, Mark C. Field, David Horn

Nature Communications 2023.12

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Optimized Workflow for Enrichment and Identification of Biotinylated Peptides Using Tamavidin 2-REV for BioID and Cell Surface Proteomics

Kohei Nishino, Harunori Yoshikawa, Kou Motani, Hidetaka Kosako

Journal of Proteome Research (American Chemical Society (ACS)) 2022.08

ISSN 1535-3893

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Binding of LAG-3 to stable peptide-MHC class II limits T cell function and suppresses autoimmunity and anti-cancer immunity.

Takumi Maruhashi, Daisuke Sugiura, Il-Mi Okazaki, Kenji Shimizu, Takeo K Maeda, Jun Ikubo, Harunori Yoshikawa, Katsumi Maenaka, Naozumi Ishimaru, Hidetaka Kosako, Tatsuya Takemoto, Taku Okazaki

Immunity 55 ( 5 ) 912 - 924 2022.05

Lymphocyte activation gene-3 (LAG-3) is a potent inhibitory co-receptor; yet, its functional ligand remains elusive, with distinct potential ligands identified. Here, we investigated the relative contribution of potential ligands, stable peptide-MHC class II complexes (pMHCII) and fibrinogen-like protein 1 (FGL1), to LAG-3 activity in vitro and in vivo. Binding of LAG-3 to stable pMHCII but not to FGL1 induced T cell suppression in vitro. Consistently, LAG-3 mutants lacking FGL1-binding capacity but not those lacking stable pMHCII-binding capacity retained suppressive activity in vitro. Accordingly, targeted disruption of stable pMHCII- but not FGL1-binding capacity of LAG-3 in NOD mice recapitulated diabetes exacerbation by LAG-3 deficiency. Additionally, the loss of stable pMHCII-binding capacity of LAG-3 augmented anti-cancer immunity comparably with LAG-3 deficiency in C57BL/6 mice. These results identify stable pMHCII as a functional ligand of LAG-3 both in autoimmunity and anti-cancer immunity. Thus, stable pMHCII-LAG-3 interaction is a potential therapeutic target in human diseases.

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Identification and validation of new ERK substrates by phosphoproteomic technologies including Phos-tag SDS-PAGE.

Harunori Yoshikawa, Kohei Nishino, Hidetaka Kosako

Journal of proteomics 258 104543 - 104543 2022.04

The extracellular signal-regulated kinase (ERK), a member of the mitogen-activated protein (MAP) kinase family, governs various cellular processes by phosphorylating a large set of substrates. Although many studies have expanded the number of ERK substrates, it is likely that additional substrates remain to be discovered. Here we have employed a quantitative phosphoproteomic approach to explore novel ERK substrates in NIH3T3 fibroblasts stably expressing a fusion protein between B-Raf and estrogen receptor. Among ERK-dependent phosphorylation targets, we focused on NGFI-A-binding protein 2 (Nab2), forkhead box protein K1 (Foxk1), and Disks large-associated protein 5 (Dlgap5/HURP). Phos-tag SDS-PAGE followed by Western blotting confirmed ERK-dependent phosphorylation of these three proteins in cells. Phos-tag SDS-PAGE of in vitro kinase assay samples revealed high degrees of phosphorylation of these proteins by active ERK. Furthermore, in-gel digestion of the phosphorylated protein bands from Phos-tag SDS-PAGE followed by LC-MS/MS indicated that active ERK directly phosphorylates the same sites in vitro as those observed in cells. This study demonstrates the usefulness of Phos-tag SDS-PAGE for validation of candidate substrates of protein kinases. SIGNIFICANCE: Label-free quantitative phosphoproteomics identified 1439 phosphopeptides derived from 840 proteins that were significantly increased by ERK activation in mouse fibroblasts. Through gene ontology and pathway analysis, we selected three proteins involved in transcriptional regulation and/or tumorigenesis. The identified phosphorylation sites of these proteins conform to the ERK consensus motif and were directly phosphorylated by active ERK in vitro. Phos-tag SDS-PAGE was useful for detecting ERK-mediated phosphorylation of these substrates both in cells and in vitro. Further characterization of these new ERK substrates will be needed to better understand the ERK signaling pathway, and our phosphoproteomic data provide useful information for studying downstream substrates of ERK.

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Genetic variation at mouse and human ribosomal DNA influences associated epigenetic states.

Francisco Rodriguez-Algarra, Robert A E Seaborne, Amy F Danson, Selin Yildizoglu, Harunori Yoshikawa, Pui Pik Law, Zakaryya Ahmad, Victoria A Maudsley, Ama Brew, Nadine Holmes, Mateus Ochôa, Alan Hodgkinson, Sarah J Marzi, Madapura M Pradeepa, Matthew Loose, Michelle L Holland, Vardhman K Rakyan

Genome biology 23 ( 1 ) 54 - 54 2022.02

BACKGROUND: Ribosomal DNA (rDNA) displays substantial inter-individual genetic variation in human and mouse. A systematic analysis of how this variation impacts epigenetic states and expression of the rDNA has thus far not been performed. RESULTS: Using a combination of long- and short-read sequencing, we establish that 45S rDNA units in the C57BL/6J mouse strain exist as distinct genetic haplotypes that influence the epigenetic state and transcriptional output of any given unit. DNA methylation dynamics at these haplotypes are dichotomous and life-stage specific: at one haplotype, the DNA methylation state is sensitive to the in utero environment, but refractory to post-weaning influences, whereas other haplotypes entropically gain DNA methylation during aging only. On the other hand, individual rDNA units in human show limited evidence of genetic haplotypes, and hence little discernible correlation between genetic and epigenetic states. However, in both species, adjacent units show similar epigenetic profiles, and the overall epigenetic state at rDNA is strongly positively correlated with the total rDNA copy number. Analysis of different mouse inbred strains reveals that in some strains, such as 129S1/SvImJ, the rDNA copy number is only approximately 150 copies per diploid genome and DNA methylation levels are < 5%. CONCLUSIONS: Our work demonstrates that rDNA-associated genetic variation has a considerable influence on rDNA epigenetic state and consequently rRNA expression outcomes. In the future, it will be important to consider the impact of inter-individual rDNA (epi)genetic variation on mammalian phenotypes and diseases.

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Efficient and Rapid Analysis of Polysomes and Ribosomal Subunits in Cells and Tissues Using Ribo Mega-SEC.

Harunori Yoshikawa, Ramasubramanian Sundaramoorthy, Daniel Mariyappa, Hao Jiang, Angus I Lamond

Bio-protocol 11 ( 15 ) e4106 2021.08

Polysome profile analysis is a popular method for separating polysomes and ribosomal subunits and is typically achieved using a sucrose density gradient (SDG). This has remained the gold standard method since ribosomes were first discovered; however, this method is time-consuming and requires multiple steps from making the gradient and long ultracentrifugation to collecting and analyzing the fractions. Each of these steps in the SDG workflow can introduce potential technical variation that affects the reproducibility of gradient profiles between samples. To address these limitations, we have developed a flexible, alternative approach for analyzing polysomes and ribosomal subunits based on size-exclusion chromatography (SEC), termed 'Ribo Mega-SEC.' In comparison with the SDG method, Ribo Mega-SEC involves a single step using ultra-high-performance liquid chromatography (uHPLC). The entire workflow, from injecting the lysate to collecting the fractions, can be performed in as little as 15 min, with high reproducibility. By varying the pore size of the SEC column, polysomes and ribosomal subunits can be separated using extracts from either human or mouse cultured cell lines or from tissue samples, Drosophila embryos, or budding yeast. The resulting separated fractions are suitable for analysis using a wide range of subsequent analytical techniques including mass spectrometry (MS)-based proteomics, RNA-Seq, electron microscopy (EM), and multiple biochemical assays.

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Upregulation of RNA cap methyltransferase RNMT drives ribosome biogenesis during T cell activation

Galloway, A., Kaskar, A., Ditsova, D., Atrih, A., Yoshikawa, H., Gomez-Moreira, C., Suska, O., Warminski, M., Grzela, R., Lamond, A.I., Darzynkiewicz, E., Jemielity, J., Cowling, V.H.

Nucleic Acids Research (Oxford University Press ({OUP})) 49 ( 12 ) 2021.06

ISSN 1362-4962

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Erosion of human X chromosome inactivation causes major remodeling of the iPSC proteome.

Alejandro J Brenes, Harunori Yoshikawa, Dalila Bensaddek, Bogdan Mirauta, Daniel Seaton, Jens L Hukelmann, Hao Jiang, Oliver Stegle, Angus I Lamond

Cell reports 35 ( 4 ) 109032 - 109032 2021.04

X chromosome inactivation (XCI) is a dosage compensation mechanism in female mammals whereby transcription from one X chromosome is repressed. Analysis of human induced pluripotent stem cells (iPSCs) derived from female donors identified that low levels of XIST RNA correlated strongly with erosion of XCI. Proteomic analysis, RNA sequencing (RNA-seq), and polysome profiling showed that XCI erosion resulted in amplified RNA and protein expression from X-linked genes, providing a proteomic characterization of skewed dosage compensation. Increased protein expression was also detected from autosomal genes without an mRNA increase, thus altering the protein-RNA correlation between the X chromosome and autosomes. XCI-eroded lines display an ∼13% increase in total cell protein content, with increased ribosomal proteins, ribosome biogenesis and translation factors, and polysome levels. We conclude that XCI erosion in iPSCs causes a remodeling of the proteome, affecting the expression of a much wider range of proteins and disease-linked loci than previously realized.

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LYAR potentiates rRNA synthesis by recruiting BRD2/4 and the MYST-type acetyltransferase KAT7 to rDNA

Keiichi Izumikawa, Hideaki Ishikawa, Harunori Yoshikawa, Sally Fujiyama, Akira Watanabe, Hiroyuki Aburatani, Hiroyuki Tachikawa, Toshiya Hayano, Yutaka Miura, Toshiaki Isobe, Richard J Simpson, Li Li, Jinrong Min, Nobuhiro Takahashi

Nucleic Acids Research (Oxford University Press ({OUP})) 47 ( 19 ) 10357 - 10372 2019.09

Accepted

Activation of ribosomal RNA (rRNA) synthesis is pivotal during cell growth and proliferation, but its aberrant upregulation may promote tumorigenesis. Here, we demonstrate that the candidate oncoprotein, LYAR, enhances ribosomal DNA (rDNA) transcription. Our data reveal that LYAR binds the histone-associated protein BRD2 without involvement of acetyl-lysine-binding bromodomains and recruits BRD2 to the rDNA promoter and transcribed regions via association with upstream binding factor. We show that BRD2 is required for the recruitment of the MYST-type acetyltransferase KAT7 to rDNA loci, resulting in enhanced local acetylation of histone H4. In addition, LYAR binds a complex of BRD4 and KAT7, which is then recruited to rDNA independently of the BRD2-KAT7 complex to accelerate the local acetylation of both H4 and H3. BRD2 also helps recruit BRD4 to rDNA. By contrast, LYAR has no effect on rDNA methylation or the binding of RNA polymerase I subunits to rDNA. These data suggest that LYAR promotes the association of the BRD2-KAT7 and BRD4-KAT7 complexes with transcription-competent rDNA loci but not to transcriptionally silent rDNA loci, thereby increasing rRNA synthesis by altering the local acetylation status of histone H3 and H4.

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Efficient analysis of mammalian polysomes in cells and tissues using ribo mega-SEC

Yoshikawa, H., Larance, M., Harney, D.J., Sundaramoorthy, R., Ly, T., Owen-Hughes, T., Lamond, A.I.

eLife 7 2018.08

Accepted, ISSN 2050-084X

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An evolutionarily conserved ribosome-rescue pathway maintains epidermal homeostasis

Liakath-Ali, Kifayathullah, Mills, Eric W., Sequeira, Ines, Lichtenberger, Beate M., Pisco, Angela Oliveira, Sipila, Kalle H., Mishra, Ajay, Yoshikawa, Harunori, Wu, Colin Chih-Chien, Ly, Tony, Lamond, Angus I., Adham, Ibrahim M., Green, Rachel, Watt, Fiona M.

Nature 556 ( 7701 ) 376 - 380 2018.04

Accepted, ISSN 0028-0836

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TDP-43 stabilises the processing intermediates of mitochondrial transcripts

Keiichi Izumikawa, Yuko Nobe, Harunori Yoshikawa, Hideaki Ishikawa, Yutaka Miura, Hiroshi Nakayama, Takashi Nonaka, Masato Hasegawa, Naohiro Egawa, Haruhisa Inoue, Kouki Nishikawa, Koji Yamano, Richard J. Simpson, Masato Taoka, Yoshio Yamauchi, Toshiaki Isobe, Nobuhiro Takahashi

SCIENTIFIC REPORTS (NATURE PUBLISHING GROUP) 7 ( 1 ) 2017.08

Accepted, ISSN 2045-2322

The 43-kDa trans-activating response region DNA-binding protein 43 (TDP-43) is a product of a causative gene for amyotrophic lateral sclerosis (ALS). Despite of accumulating evidence that mitochondrial dysfunction underlies the pathogenesis of TDP-43-related ALS, the roles of wild-type TDP-43 in mitochondria are unknown. Here, we show that the small TDP-43 population present in mitochondria binds directly to a subset of mitochondrial tRNAs and precursor RNA encoded in L-strand mtDNA. Upregulated expression of TDP-43 stabilised the processing intermediates of mitochondrial polycistronic transcripts and their products including the components of electron transport and 16S mt-rRNA, similar to the phenotype observed in cells deficient for mitochondrial RNase P. Conversely, TDP-43 deficiency reduced the population of processing intermediates and impaired mitochondrial function. We propose that TDP-43 has a novel role in maintaining mitochondrial homeostasis by regulating the processing of mitochondrial transcripts.

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Poly(A)-specific ribonuclease regulates the processing of small-subunit rRNAs in human cells

Hideaki Ishikawa, Harunori Yoshikawa, Keiichi Izumikawa, Yutaka Miura, Masato Taoka, Yuko Nobe, Yoshio Yamauchi, Hiroshi Nakayama, Richard J. Simpson, Toshiaki Isobe, Nobuhiro Takahashi

NUCLEIC ACIDS RESEARCH (OXFORD UNIV PRESS) 45 ( 6 ) 3437 - 3447 2017.04

Accepted, ISSN 0305-1048

Ribosome biogenesis occurs successively in the nucleolus, nucleoplasm, and cytoplasm. Maturation of the ribosomal small subunit is completed in the cytoplasm by incorporation of a particular class of ribosomal proteins and final cleavage of 18S-E prerRNA (18S-E). Here, we show that poly(A)-specific ribonuclease (PARN) participates in steps leading to 18S-E maturation in human cells. We found PARN as a novel component of the pre-40S particle pulled down with the pre-ribosome factor LTV1 or Bystin. Reverse pull-down analysis revealed that PARN is a constitutive component of the Bystin-associated pre-40S particle. Knockdown of PARN or exogenous expression of an enzyme-dead PARN mutant (D28A) accumulated 18S-E in both the cytoplasm and nucleus. Moreover, expression of D28A accumulated 18S-E in Bystin-associated pre-40S particles, suggesting that the enzymatic activity of PARN is necessary for the release of 18S-E from Bystin-associated pre-40S particles. Finally, RNase H-based fragmentation analysis and 3'-sequence analysis of 18S-E species present in cells expressing wild-type PARN or D28A suggested that PARN degrades the extended regions encompassing nucleotides 5-44 at the 3' end of mature 18S rRNA. Our results reveal a novel role for PARN in ribosome biogenesis in human cells.

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Chtop (Chromatin target of Prmt1) auto-regulates its expression level via intron retention and nonsense-mediated decay of its own mRNA

Keiichi Izumikawa, Harunori Yoshikawa, Hideaki Ishikawa, Yuko Nobe, Yoshio Yamauchi, Sjaak Philipsen, Richard J. Simpson, Toshiaki Isobe, Nobuhiro Takahashi

NUCLEIC ACIDS RESEARCH (OXFORD UNIV PRESS) 44 ( 20 ) 9847 - 9859 2016.11

Accepted, ISSN 0305-1048

Chtop (chromatin target of Prmt1) regulates various aspects of gene expression including transcription and mRNA export. Despite these important functions, the regulatory mechanism underlying Chtop expression remains undetermined. Using Chtop-expressing human cell lines, we demonstrate that Chtop expression is controlled via an autoregulatory negative feedback loop whereby Chtop binds its own mRNA to retain intron 2 during splicing; a premature termination codon present at the 5' end of intron 2 leads to nonsense-mediated decay of the mRNA. We also show that Chtop interacts with exon 2 of Chtop mRNA via its arginine-glycine-rich (RG) domain, and with intron 2 via its N-terminal (N1) domain; both are required for retention of intron 2. In addition, we show that hnRNP H accelerates intron 2 splicing of Chtop mRNA in a manner dependent on Chtop expression level, suggesting that Chtop and hnRNP H regulate intron 2 retention of Chtop mRNA antagonistically. Thus, the present study provides a novel molecular mechanism by which mRNA and protein levels are constitutively regulated by intron retention.

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Collaborator of alternative reading frame protein (CARF) regulates early processing of pre-ribosomal RNA by retaining XRN2 (5 '-3 ' exoribonuclease) in the nucleoplasm

Shigeko Sato, Hideaki Ishikawa, Harunori Yoshikawa, Keiichi Izumikawa, Richard J. Simpson, Nobuhiro Takahashi

NUCLEIC ACIDS RESEARCH (OXFORD UNIV PRESS) 43 ( 21 ) 10397 - 10410 2015.12

Accepted, ISSN 0305-1048

Collaborator of alternative reading frame protein (CARF) associates directly with ARF, p53, and/or human double minute 2 protein (HDM2), a ubiquitin-protein ligase, without cofactors and regulates cell proliferation by forming a negative feedback loop. Although ARF, p53, and HDM2 also participate in the regulation of ribosome biogenesis, the involvement of CARF in this process remains unexplored. In this study, we demonstrate that CARF associates with 5'-3' exoribonuclease 2 (XRN2), which plays a major role in both the maturation of rRNA and the degradation of a variety of discarded pre-rRNA species. We show that overexpression of CARF increases the localization of XRN2 in the nucleoplasm and a concomitant suppression of pre-rRNA processing that leads to accumulation of the 5' extended from of 45S/47S pre-rRNA and 5'-01, A0-1 and E-2 fragments of pre-rRNA transcript in the nucleolus. This was also observed upon XRN2 knockdown. Knockdown of CARF increased the amount of XRN2 in the nucleolar fraction as determined by cell fractionation and by immnocytochemical analysis. These observations suggest that CARF regulates early steps of pre-rRNA processing during ribosome biogenesis by controlling spatial distribution of XRN2 between the nucleoplasm and nucleolus.

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Plant Raf-like kinase integrates abscisic acid and hyperosmotic stress signaling upstream of SNF1-related protein kinase2

Masashi Saruhashi, Totan Kumar Ghosh, Kenta Arai, Yumiko Ishizaki, Kazuya Hagiwara, Kenji Komatsu, Yuh Shiwa, Keiichi Izumikawa, Harunori Yoshikawa, Taishi Umezawa, Yoichi Sakata, Daisuke Takezawa

PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA (NATL ACAD SCIENCES) 112 ( 46 ) E6388 - E6396 2015.11

Accepted, ISSN 0027-8424

Plant response to drought and hyperosmosis is mediated by the phytohormone abscisic acid (ABA), a sesquiterpene compound widely distributed in various embryophyte groups. Exogenous ABA as well as hyperosmosis activates the sucrose nonfermenting 1 (SNF1)-related protein kinase2 (SnRK2), which plays a central role in cellular responses against drought and dehydration, although the details of the activation mechanism are not understood. Analysis of a mutant of the moss Physcomitrella patens with reduced ABA sensitivity and reduced hyperosmosis tolerance revealed that a protein kinase designated "ARK" (for "ABA and abiotic stress-responsive Raf-like kinase") plays an essential role in the activation of SnRK2. ARK encoded by a single gene in P. patens belongs to the family of group B3 Raf-like MAP kinase kinase kinases (B3-MAPKKKs) mediating ethylene, disease resistance, and salt and sugar responses in angiosperms. Our findings indicate that ARK, as a novel regulatory component integrating ABA and hyperosmosis signals, represents the ancestral B3-MAPKKKs, which multiplied, diversified, and came to have specific functions in angiosperms.

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