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| 1.
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Nainu, Firzan ; Shiratsuchi, Akiko ; Nakanishi, Yoshinobu ; 白土, 明子 ; 中西, 義信
概要:
金沢大学医薬保健研究域薬学系<br />Viruses are infectious entities that hijack host replication machineries to produce their progeny, r
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esulting, in most cases, in disease and, sometimes, in death in infected host organisms. Hosts are equipped with an array of defense mechanisms that span from innate to adaptive as well as from humoral to cellular immune responses. We previously demonstrated that mouse cells underwent apoptosis in response to influenza virus infection. These apoptotic, virus-infected cells were then targeted for engulfment by macrophages and neutrophils. We more recently reported similar findings in the fruit fly Drosophila melanogaster, which lacks adaptive immunity, after an infection with Drosophila C virus. In these experiments, the inhibition of phagocytosis led to severe influenza pathologies in mice and early death in Drosophila. Therefore, the induction of apoptosis and subsequent phagocytosis of virus-infected cells appear to be an antiviral innate immune mechanism that is conserved among multicellular organisms. We herein discuss the underlying mechanisms and significance of the apoptosis-dependent phagocytosis of virus-infected cells. Investigations on the molecular and cellular features responsible for this underrepresented virus-host interaction may provide a promising avenue for the discovery of novel substances that are targeted in medical treatments against virus-induced intractable diseases. © 2017 Nainu, Shiratsuchi and Nakanishi.
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| 2.
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Nakanishi, Yoshinobu ; Hashimoto, Yumi ; Takizawa, Takenori ; Shiratsuchi, Akiko
概要:
金沢大学医薬保健研究域薬学系<br />Influenza virus-infected cells are induced to undergo apoptosis and become susceptible to phagocytos
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is. Data from our in vitro and in vivo experiments have suggested that 1) alveolar macrophages and neutrophils phagocytose influenza virus-infected cells in an apoptosis-dependent manner; 2) the membrane phospholipid phosphatidylserine and viral neuraminidase-processed carbohydrates at the surface of target cells and phagocytes, respectively, are involved in the association of the two types of cells; and 3) phagocytic elimination of virus-infected cells leads to a reduction in the pathogenesis of influenza. These findings could lead to the development of a novel antiviral agent against influenza. © 2008 Bentham Science Publishers Ltd.全文公開200906
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| 3.
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Kuraishi, Takayuki ; Nakagawa, Yukiko ; Nagaosa, Kazushige ; Hashimoto, Yumi ; Ishimoto, Takashi ; Moki, Takeshi ; Fujita, Yu ; Nakayama, Hiroshi ; Dohmae, Naoshi ; Shiratsuchi, Akiko ; Yamamoto, Nakako ; Ueda, Koichi ; Yamagichi, Masamitsu ; Awasaki, Takeshi ; Nakanishi, Yoshinobu
概要:
金沢大学医薬保健研究域薬学系<br />Phagocytic removal of cells undergoing apoptosis is necessary for animal development and tissue home
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ostasis. Draper, a homologue of the Caenorhabditis elegans phagocytosis receptor CED-1, is responsible for the phagocytosis of apoptotic cells in Drosophila, but its ligand presumably present on apoptotic cells remains unknown. An endoplasmic reticulum protein that binds to the extracellular region of Draper was isolated. Loss of this protein, which we name Pretaporter, led to a reduced level of apoptotic cell clearance in embryos, and the overexpression of pretaporter in the mutant flies rescued this defect. Results from genetic analyses suggested that Pretaporter functionally interacts with Draper and the corresponding signal mediators. Pretaporter was exposed at the cell surface after the induction of apoptosis, and cells artificially expressing Pretaporter at their surface became susceptible to Draper-mediated phagocytosis. Finally, the incubation with Pretaporter augmented the tyrosine-phosphorylation of Draper in phagocytic cells. These results collectively suggest that Pretaporter relocates from the endoplasmic reticulum to the cell surface during apoptosis to serve as a ligand for Draper in the phagocytosis of apoptotic cells. © 2009 European Molecular Biology Organization.
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| 4.
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Nishida, Jun ; Shiratsuchi, Akiko ; Nadano, Daita ; Sato, Takaaki ; Nakanishi, Yoshinobu
概要:
金沢大学医薬保健研究域薬学系<br />Changes in the amount and localization of human ribosomal proteins during apoptosis were determined.
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When total lysates of Jurkat cells undergoing apoptosis induced by doxorubicin were analyzed by Western blotting, degradation of three ribosomal proteins, S18, L5, and L14, was detected at 48 h after the induction of apoptosis. Decreases in the amounts of these three ribosomal proteins were also observed in ribosome-enriched fractions. These changes were partly abolished by the addition of the pan-caspase inhibitor z-VAD-fmk. Moreover, formation of the 80S ribosome complex appeared to be inhibited at 48 h after apoptosis induction. On the other hand, the rate of protein synthesis, assessed by measuring the incorporation of [35S]Met into bulk proteins, decreased as early as 12 h after the addition of doxorubicin. These results indicate that changes in the amount of ribosomal proteins and the overall structure of ribosomes in apoptosing cells occur after protein synthesis declines. Finally, analyses by flow cytometry, immunofluorescence, and Western blotting showed that six ribosomal proteins, S15, PO, L5, L6, L36a, and L41, were relocalized and expressed at the cell surface during apoptosis. The above results collectively indicate that ribosomes are structurally altered in apoptotic cells following inactivation of protein synthesis.
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| 5.
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Nakai, Yuji ; Nomura, Yoshitaka ; Sato, Toshihiro ; Shiratsuchi, Akiko ; Nakanishi, Yoshinobu
概要:
金沢大学医薬保健研究域薬学系<br />To elucidate the molecular basis of the binding of proteins to the membrane phospholipid phosphatidy
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lserine (PS), we characterized PS-binding peptides isolated from a phage display library. Amino acid sequences deduced from the nucleotide sequences of over 60 phage clones isolated revealed that there was no common primary structure among these peptides, but all peptides were rich in basic amino acid residues. In particular, 15 clones encoded peptides that contained contiguous arginine residues. Characterization of two such peptides in more detail showed that they bound to PS, and to a much lower extent to other phospholipids, including phosphatidylinositol, phosphatidylethanolamine, and phosphatidylcholine. Unlike other Ca2+-dependent PS-binding proteins, these peptides did not require Ca2+ for binding to PS, and the addition of Ca2+ did not alter the phospholipid specificity. Substitution of one of the two RR sequences in one peptide by alanine had no effect, but that of both sequences completely abolished the activity. Furthermore, we identified a Drosophila gene coding for a presumed nuclear protein that shares an amino acid sequence, including a RR residue, with one of the two PS-binding peptides. This protein bound to PS partly depending on the presence of the RR residue. These results allowed us to conclude that an amino acid sequence including contiguous arginine residues is a novel motif that defines Ca2+-independent PS-binding activity. © 2005 The Japanese Biochemical Society.
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| 6.
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Shiratsuchi, Akiko ; Mori, Tomoe ; Takahashi, Yae ; Sakai, Koichiro ; Nakanishi, Yoshinobu
概要:
金沢大学医薬保健研究域薬学系<br />The structure and subcellular localization of a number of molecules change during apoptosis. These m
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olecules are recognized by the immune system, leading to the development of autoimmunity when apoptotic cells fail to be effectively cleared by phagocytosis. We searched for such molecules by analyzing sera from 12 individuals who suffered from autoimmune diseases and from 3 patients with amyotrophic lateral sclerosis. One serum sample, designated 681, detected an antigen that fulfilled the above criteria. In Western blotting of lysates of human Jurkat T cells, the 681 antigen appeared as a distinct signal with a molecular mass of 60 kDa in normal cells, and 2 additional signals with faster mobilities were detected in apoptotic cells. The results of subcellular fractionation and immunofluorescence experiments revealed this antigen to be strictly localized in the nucleus of normal cells, but to be translocated to a region near the plasma membrane, to membrane blebs in particular, after the induction of apoptosis. Under conditions in which membrane blebbing was inhibited in apoptotic cells, the antigen still moved away from the nucleus, but its accumulation at the periplasmic region was completely abolished. The apparent partial cleavage and intracellular redistribution of the 681 antigen in apoptotic cells mimics changes previously reported for the nuclear autoantigen La, but the 681 antigen was clearly distinct from La. These results suggest that cleavage-dependent exit from the nucleus during apoptosis is a phenomenon common to nuclear autoantigens.
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| 7.
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Takizawa, Takenori ; Tatematsu, Chizuru ; Watanabe, Kimi ; Kato, Kanefusa ; Nakanishi, Yoshinobu
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金沢大学医薬保健研究域薬学系<br />Calnexin is an endoplasmic reticulum (ER)-resident molecular chaperone that plays an essential role
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in the correct folding of membrane proteins. We found that calnexin is subjected to partial cleavage in apoptotic mouse cells. Both ER stress-inducing and ER stress-non-inducing apoptotic stimuli caused the cleavage of calnexin, indicating that this event does not always occur downstream of ER stress. The inhibition of caspases that target the amino acid sequence DXXD abrogated calnexin cleavage in apoptotic stimulus-treated cells. In addition, disruption of one of two DXXD sequences located in the cytoplasmic domain caused calnexin to escape cleavage during apoptosis. Furthermore, calnexin was cleaved in vitro by recombinant caspase-3 or caspase-7. Finally, the overexpression of a presumed cleavage product of calnexin partly inhibited apoptosis. These results collectively suggest that caspase-3 or caspase-7 cleaves calnexin, whose cleaved product leads to the attenuation of apoptosis.
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| 8.
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Shiratsuchi, Akiko ; Mori, Tomoe ; Nakanishi, Yoshinobu
概要:
金沢大学医薬保健研究域薬学系<br />Plasma membrane blebs are observed in many types of apoptotic cells, but their physiological roles r
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emain to be clarified. We examined whether there is a causative connection between membrane blebbing and other apoptotic changes in Jurkat cells induced to undergo apoptosis by doxorubicin in the presence or absence of Y-27632, an inhibitor of the Rho kinase ROCK-I. The inclusion of the drug made most membrane blebs disappear, while other changes, such as chromatin condensation, inactivation of mitochondrial enzymes, externalization of the membrane phospholipid phosphatidylserine, and removal of cell surface sialic acid, remained unaffected. Furthermore, these apoptotic cells were phagocytosed by macrophages as efficiently as normally apoptosing cells. These results indicate that blebbing of the plasma membrane occurs independently from other apoptotic changes and is not involved in the recognition and engulfment of apoptotic cells by macrophages.
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| 9.
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Wakisaka, Naohiro ; Yoshizaki, Tomokazu ; Raab-Traub, Nancy ; Pagano, Joseph S.
概要:
金沢大学医学部附属病院耳鼻咽喉科<br />In nasopharyngeal carcinoma (NPC), Epstein-Barr virus (EBV) infection is mainly latent, and the tu
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mor cells contain episomal viral DNA. We have shown that the acyclic nucleoside phosphonate analog, cidofovir [(S)-1-(3-hydroxy-2- (phosphonylmethoxypropyl)cytosine] (HPMPC), inhibits growth of NPC xenografts in nude mice by causing apoptosis. The ribonucleotide reductase (RR) inhibitors, hydroxyurea and didox (3,4-dihydroxybenzohydroxamic acid), have been demonstrated to inhibit neoplastic growth and are used as antiviral and anticancer agents. Here we show that RR inhibitors enhance the antitumor effect of cidofovir in EBV-transformed epithelial cells. MTT assays indicate that hydroxyurea and didox enhance cidofovir-induced cell toxicity in NPC-KT cells, an EBV-positive epithelial cell line derived from NPC. The effect is due to enhancement of apoptosis through the caspase cascade as shown by pronounced cleavage of poly(ADP-ribose) polymerase. Finally, hydroxyurea strikingly enhanced the cidofovir-induced growth-inhibitory effect on NPC grown in athymic mice. The results suggest that RR inhibitors should enhance the antitumor effect of acyclic nucleoside phosphonate analogs on NPC. © 2005 Wiley-Liss, Inc.
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| 10.
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Harada, Kenichi ; Nakanuma, Yasuni
概要:
金沢大学大学院医学系研究科がん細胞学<br />Primary biliary cirrhosis (PBC) is histologically characterized by chronic nonsuppurative destru
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ctive cholangitis (CNSDC) and the progressive loss of intrahepatic small bile ducts. Cellular immune mechanisms involving T-cell reaction are thought to be significantly involved in the formation of CNSDC and bile duct loss. In inflamed portal tracts of PBC, CD4+ T cells of Th1 type expressing IFN-γ or CXCR3 are aggregated and more commonly detected around injured bile ducts than Th2-type CD4+ T cells expressing IL-4 or CCR4, indicating that Th1-dominant cellular immunity plays a more-prominent role in recruitment of memory T-cell subsets in PBC and may be responsible for the progressive bile duct damage. Biliary epithelial apoptosis is demonstrated to be a major pathogenic process of bile duct loss in PBC. In CNSDC, several biliary apoptotic cells, an aberrant expression of Fas antigen (proapoptotic molecule) and decreased expression of bcl-2 and mcl-1 (antiapoptotic molecules) are found, although interlobular bile ducts express bcl-2 and mcl-2 but lack Fas. In addition, the upregulation of WAF1 and p53 related to biliary apoptosis is found in biliary epithelial cells of PBC, which may be due to cell senescence in response to genotoxic damage such as oxidative stress. Several steps and mechanisms during induction and progression of cholangitis and biliary apoptosis followed by bile duct loss are now being proposed in PBC, but future analysis of an etiopathogenesis to explain the characteristic histopathogenesis of PBC is required. © 2006 The Japanese Society for Clinical Molecular Morphology.
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