Kentaro Hanada

National Institute of Infectious Diseases, Tokyo, Edo, Tōkyō, Japan

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Publications (113)504.53 Total impact

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    ABSTRACT: Hepatitis C virus (HCV) entry into host cells is a complex process requiring multiple host factors, including claudin-1 (CLDN1). Safe and effective therapeutic entry inhibitors need to be developed. We isolated a human hepatic Huh7.5.1-derived cell mutant nonpermissive to HCV, and comparative microarray analysis showed that the mutant was CLDN1 defective. Four hybridomas were obtained, which produced monoclonal antibodies (mAbs) that interacted with the parental Huh7.5.1 cell but not with the CLDN1-defective mutant. All mAbs produced by these hybridomas specifically bound to human CLDN1 with very high affinity and prevented HCV infection of Huh7.5.1 cells in a dose-dependent manner, without apparent cytotoxicity. Two selected mAbs also inhibited HCV infection of human liver-chimeric mice without significant adverse effects. CLDN1 may be a potential target to prevent HCV infection in vivo. Anti-CLDN1 mAbs may hence be promising candidates as novel anti-HCV agents. Safe and effective therapeutic entry inhibitors against Hepatitis C virus (HCV) are very useful for combination therapies with other anti-HCV drugs such as direct-acting antivirals. In this study, we first showed the effective strategy to develop functional monoclonal antibodies (mAbs) against extracellular domains of a multimembrane-spanning target protein, claudin-1 (CLDN1), using parental cells expressing the intact target membrane protein and the target-defective cells. The established mAbs against CLDN1, which had very high affinity with intact CLDN1, efficiently inhibited in vitro and in vivo HCV infection. These anti-CLDN1 mAbs are promising leads for novel entry inhibitors against HCV. Copyright © 2015, American Society for Microbiology. All Rights Reserved.
    Journal of Virology 02/2015; 89(9). DOI:10.1128/JVI.03676-14 · 4.65 Impact Factor
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    ABSTRACT: Based on multipurpose cohort studies, coffee consumption reduces the risk of hepatocellular carcinoma, one of the main causes of which is hepatitis C virus (HCV) infection. Here, we focused on the effect of caffeic acid, a major organic acid derived from coffee, on the propagation of HCV using an in vitro naïve HCV particle-infection and production system within human hepatoma-derived Huh7.5.1-8 cells. When cells were treated with 1% coffee extract or 0.1% caffeic acid for 1-h after HCV infection, the amount of HCV particles released into the medium at 3 and 4 days post-infection were considerably decreased. HCV-infected cells were cultured with 0.001% caffeic acid for 4 days, which was sufficient to decrease the amount of HCV particles released into the medium. Caffeic acid treatment inhibited the initial stage of HCV infection, i.e., between virion entry and the translation of the RNA genome. This inhibitory effect was observed against both HCV genotypes 1b and 2a. These results suggested that treatment of cells with caffeic acid inhibited HCV propagation.
    Japanese journal of infectious diseases 01/2015; DOI:10.7883/yoken.JJID.2014.309 · 1.20 Impact Factor
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    ABSTRACT: ATP binding cassette protein B4 (ABCB4), which is specifically expressed on the canalicular membrane of hepatocytes, exports phosphatidylcholine (PC) into bile. Because sphingomyelin (SM) depletion increases cellular PC content and stimulates PC and cholesterol efflux by ABCA1, a key transporter involved in generation of high density lipoprotein, we predicted that SM depletion also stimulates PC efflux through ABCB4. To test this prediction, we compared the lipid efflux activity of ABCB4 and ABCA1 under SM depletion induced by two different types of inhibitors for SM synthesis, myriocin and HPA-12, in HEK293 and BHK cells. Unexpectedly, SM depletion exerted opposite effects on ABCB4 and ABCA1, suppressing PC efflux through ABCB4 while stimulating efflux through ABCA1. Both ABCB4 and ABCA1 were recovered from Triton X-100-soluble membranes, but ABCB4 was mainly recovered from CHAPS-insoluble SM-rich membranes, whereas ABCA1 was recovered from CHAPS-soluble membranes. These results suggest that a SM-rich membrane environment is required for ABCB4 to function. ABCB4 must have evolved to exert its maximum activity in the SM-rich membrane environment of the canalicular membrane, where it transports PC as the physiological substrate. Copyright © 2015, The American Society for Biochemistry and Molecular Biology.
    The Journal of Lipid Research 01/2015; 56(3). DOI:10.1194/jlr.M056622 · 4.73 Impact Factor
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    ABSTRACT: Hepatitis C virus (HCV) exploits host membrane cholesterol and its metabolism for progeny virus production. Here, we examined the impact of targeting cellular squalene synthase (SQS), the first committed enzyme for cholesterol biosynthesis, on HCV production. By using the HCV JFH-1 strain and human hepatoma Huh-7.5.1-derived cells, we found that SQS inhibitors, YM-53601 and zaragozic acid A, decreased viral RNA, protein, and progeny production in HCV-infected cells without affecting cell viability. Similarly, siRNA-mediated knockdown of SQS led to significantly reduced HCV production, confirming the enzyme as an antiviral target. A metabolic labeling study demonstrated that YM-53601 suppressed the biosynthesis of cholesterol and cholesteryl esters at antiviral concentrations. Unlike YM-53601, the cholesterol esterification inhibitor Sandoz 58-035 did not exhibit an antiviral effect, suggesting that biosynthesis of cholesterol is more important for HCV production than that of cholesteryl esters. YM-53601 inhibited transient replication of a JFH-1 subgenomic replicon and entry of JFH-1 pseudoparticles, suggesting that at least suppression of viral RNA replication and entry contributes to the antiviral effect of the drug. Collectively, our findings highlight the importance of the cholesterol biosynthetic pathway in HCV production and implicate SQS as a potential target for antiviral strategies against HCV. Hepatitis C virus (HCV) is known to be closely associated with host cholesterol and its metabolism throughout the viral life cycle. However, impact of targeting cholesterol biosynthetic enzymes on HCV production is not fully understood. We found that squalene synthase, the first committed enzyme for cholesterol biosynthesis, is important for HCV production and propose this enzyme as a potential anti-HCV target. We provide evidence that synthesis of free cholesterol is more important for HCV production than that of esterified cholesterol, highlighting marked free cholesterol dependency of HCV production. Our findings also offer a new insight into a role of intracellular cholesterol pool that is coupled to its biosynthesis in HCV life cycle. Copyright © 2014, American Society for Microbiology. All Rights Reserved.
    Journal of Virology 12/2014; 89(4). DOI:10.1128/JVI.03385-14 · 4.65 Impact Factor
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    ABSTRACT: An efficient cell culture and infection system for hepatitis C virus (HCV) is useful for analyzing the complete virus life cycle. Human hepatic Huh7.5.1 cells and a HCV-JFH1 strain have been widely employed for infection experiments. Huh7.5.1 cells that we have cultured exhibited heterogeneous phenotypes of HCV infection. By single-cell cloning of Huh7.5.1 cells, we isolated a clone highly permissive to HCV and a CD81-defective clone nonpermissive to HCV, designated as Huh7.5.1-8 and Huh7.5.1-5, respectively. Expression of CD81 into Huh7.5.1-5 cells restored the permissiveness to HCV, indicating that CD81 is essential for HCV infection and a defect in CD81 causes the nonpermissiveness to HCV in Huh7.5.1-5 cells. Huh7.5.1-8 cells had about 10-fold higher HCV replication activities, with cellular HCV RNA copy numbers of >10(9) copies/μg of cellular RNA and viral titers of >10(6) infectious units/ml of culture supernatant. Permissiveness of Huh7.5.1-8 cells to HCV infection was phenotypically very stable because there was no difference in permissiveness after more than 100 passages (1-year culture). This efficient cell culture system for HCV using Huh7.5.1-8 cells provides a powerful tool for studying the HCV life cycle and constructing antiviral strategies.
    Japanese journal of infectious diseases 11/2014; 68(2). DOI:10.7883/yoken.JJID.2014.231 · 1.20 Impact Factor
  • Toshiyuki Yamaji · Kentaro Hanada
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    ABSTRACT: In recent decades, many sphingolipid enzymes, sphingolipid-metabolism regulators, and sphingolipid transfer proteins have been isolated and characterized. This review will provide an overview of the intracellular localization and topology of sphingolipid enzymes in mammalian cells to highlight the locations where respective sphingolipid species are produced. Interestingly, three sphingolipids that reside or are synthesized in cytosolic leaflets of membranes (ceramide, glucosylceramide and ceramide-1-phosphate) all have cytosolic lipid transfer proteins (LTPs). These LTPs consist of ceramide transfer protein (CERT), four-phosphate adaptor protein 2 (FAPP2) and ceramide-1-phosphate transfer protein (CPTP), respectively. These LTPs execute functions that affect both the location and metabolism of the lipids they bind. Molecular details describing the mechanisms of regulation of LTPs continue to emerge and reveal a number of critical processes, including competing phosphorylation and dephosphorylation reactions and binding interactions with regulatory proteins and lipids, that influence the transport, organelle distribution and metabolism of sphingolipids.
    Traffic 11/2014; 16(2). DOI:10.1111/tra.12239 · 4.71 Impact Factor
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    ABSTRACT: ATP-binding cassette A1 (ABCA1), ABCG1, and ABCG4 are lipid transporters that mediate the efflux of cholesterol from cells. To analyze the characteristics of these lipid transporters, we examined and compared their distributions and lipid efflux activity on the plasma membrane. The efflux of cholesterol mediated by ABCA1 and ABCG1, but not ABCG4, was affected by a reduction of cellular sphingomyelin levels. Detergent solubility and gradient density ultracentrifugation assays indicated that ABCA1, ABCG1, and ABCG4 were distributed to domains that were solubilized by Triton X-100 and Brij 96, resistant to Triton X-100 and Brij 96, and solubilized by Triton X-100 but resistant to Brij 96, respectively. Furthermore, ABCG1, but not ABCG4, was colocalized with flotillin-1 on the plasma membrane. The amounts of cholesterol extracted by methyl-β-cyclodextrin were increased by ABCA1, ABCG1, or ABCG4, suggesting that cholesterol in non-raft domains was increased. Furthermore, ABCG1 and ABCG4 disturbed the localization of caveolin-1 to the detergent-resistant domains and the binding of cholera toxin subunit B to the plasma membrane. These results suggest that ABCA1, ABCG1, and ABCG4 are localized to distinct membrane meso-domains and disturb the meso-domain structures by reorganizing lipids on the plasma membrane; collectively, these observations may explain the different substrate profiles and lipid efflux roles of these transporters.
    PLoS ONE 10/2014; 9(10):e109886. DOI:10.1371/journal.pone.0109886 · 3.23 Impact Factor
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    Kentaro Hanada
    Biochimica et Biophysica Acta (BBA) - Molecular and Cell Biology of Lipids 10/2014; 1841(10):1561–1562. DOI:10.1016/j.bbalip.2014.08.002 · 4.50 Impact Factor
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    ABSTRACT: Continuous cell lines that originate from mammalian tissues serve as not only invaluable tools for life sciences, but also important animal cell substrates for the production of various types of biological pharmaceuticals. Vero cells are susceptible to various types of microbes and toxins and have widely contributed to not only microbiology, but also the production of vaccines for human use. We here showed the genome landscape of a Vero cell line, in which 25,877 putative protein-coding genes were identified in the 2.97-Gb genome sequence. A homozygous ∼9-Mb deletion on chromosome 12 caused the loss of the type I interferon gene cluster and cyclin-dependent kinase inhibitor genes in Vero cells. In addition, an ∼59-Mb loss of heterozygosity around this deleted region suggested that the homozygosity of the deletion was established by a large-scale conversion. Moreover, a genomic analysis of Vero cells revealed a female Chlorocebus sabaeus origin and proviral variations of the endogenous simian type D retrovirus. These results revealed the genomic basis for the non-tumourigenic permanent Vero cell lineage susceptible to various pathogens and will be useful for generating new sub-lines and developing new tools in the quality control of Vero cells.
    DNA research: an international journal for rapid publication of reports on genes and genomes 09/2014; 21(6). DOI:10.1093/dnares/dsu029 · 2.35 Impact Factor
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    ABSTRACT: Mammalian cells store excess fatty acids in the form of triglycerides within lipid droplets. The intracellular bacterium Orientia tsutsugamush is the causative agent of severe human rickettiosis. We found that O. tsutsugamushi infection induces the formation of lipid droplets in mouse L-929 fibroblasts. In infected cells, a parallel increase in the number of lipid droplets and pathogens was observed. Interestingly, the pathogen-infection induced the accumulation of triglycerides even without external supply of fatty acids. These results suggest that O. tsutsugamushi alters lipid metabolism of host cells to induce lipid droplets.
    Microbes and Infection 09/2014; 16(11). DOI:10.1016/j.micinf.2014.09.004 · 2.73 Impact Factor
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    ABSTRACT: Background Progressive familial intrahepatic cholestasis type 1 (PFIC1), an inherited liver disease caused by mutations in ATP8B1, progresses to severe cholestasis with a sustained intractable itch. Currently, no effective therapy has been established for PFIC1. Decreased function of the bile salt export pump (BSEP) in hepatocytes is suggested to be responsible for the severe cholestasis observed in PFIC1. We found a previously unidentified pharmacological effect of 4-phenylbutyrate (4PB) that increases the expression and function of BSEP. Here, we tested 4PB therapy in three patients with PFIC1. Methods The therapeutic potency of 4PB in these patients was tested by oral administration of this drug with gradually increasing dosage (200, 350, and 500 mg/kg/day) for 6 months. Biochemical, histological, and clinical data were collected. Results 4PB therapy had no beneficial effect on the patients’ liver functions, as assessed by biochemical and histological analyses, despite an increase in hepatic BSEP expression. However, therapy with 4PB at a dosage of 350 or 500 mg/kg/day significantly relieved the intractable itch. Serum levels of potential pruritogens in cholestasis were much higher than the reference ranges during the 4PB therapy. Conclusions 4PB therapy may be a new medication for patients with intractable cholestatic pruritus and may improve quality of life for patients and their families.
    Orphanet Journal of Rare Diseases 07/2014; 9(1):89. DOI:10.1186/1750-1172-9-89 · 3.96 Impact Factor
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    ABSTRACT: The nucleolar protein PICT1 regulates tumor suppressor p53 by tethering ribosomal protein L11 within the nucleolus to repress the binding of L11 to the E3 ligase MDM2. PICT1 depletion results in the release of L11 to the nucleoplasm to inhibit MDM2, leading to p53 activation. Here, we demonstrate that nucleolar stress induces proteasome-mediated degradation of PICT1 in a ubiquitin-independent manner. Treatment of H1299 cells with nucleolar stress inducers, such as actinomycin D, 5-fluorouridine, or doxorubicin, induced the degradation of PICT1 protein. The proteasome inhibitors MG132, lactacystin, and epoxomicin blocked PICT1 degradation, whereas the inhibition of E1 ubiquitin-activating enzyme by a specific inhibitor and genetic inactivation fail to repress PICT1 degradation. In addition, the 20 S proteasome was able to degrade purified PICT1 protein in vitro. We also found a PICT1 mutant showing nucleoplasmic localization did not undergo nucleolar stress-induced degradation, although the same mutant underwent in vitro degradation by the 20 S proteasome, suggesting that nucleolar localization is indispensable for the stress-induced PICT1 degradation. These results suggest that PICT1 employs atypical proteasome-mediated degradation machinery to sense nucleolar stress within the nucleolus.
    Journal of Biological Chemistry 06/2014; 289(30). DOI:10.1074/jbc.M114.571893 · 4.57 Impact Factor
  • Kentaro Hanada · Dennis Voelker
    Traffic 06/2014; 15(9). DOI:10.1111/tra.12193 · 4.71 Impact Factor
  • Keigo Kumagai · Miyuki Kawano-Kawada · Kentaro Hanada
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    ABSTRACT: The ceramide transport protein CERT mediates the inter-organelle transport of ceramide for the synthesis of sphingomyelin, presumably through endoplasmic reticulum (ER)-Golgi membrane contact sites. CERT has a short peptide motif named FFAT, which associates with the ER-resident membrane protein VAP. We here showed that the phosphorylation of CERT at serine-315 (S315), which is adjacent to the FFAT motif, markedly enhanced the interaction of CERT with VAP. The phosphomimetic CERT S315E mutant exhibited higher activity to support the ER-to-Golgi transport of ceramide than the wild-type control in a semi-intact cell system, and this enhanced activity was abrogated when its FFAT motif was deleted. The level of phosphorylation of CERT at S315 increased in HeLa cells treated with a sphingolipid biosynthesis inhibitor or exogenous sphingomyelinase. Expression of CERT S315E induced intracellular punctate structures, to which CERT and VAP were co-localized, and the occurrence of the structure was dependent on both phosphatidylinositol 4-monophosphate binding and VAP binding activities of CERT. Phosphorylation of another region (named a serine rich motif; SRM) in CERT is known to down-regulate the activity of CERT. Analysis of various CERT mutant constructs showed that the de-phosphorylation of the SRM and the phosphorylation of S315 likely have the additive contribution to enhance the activity of CERT. These results demonstrate that the phosphorylation of CERT at the FFAT motif-adjacent serine affected its affinity for VAP, which may regulate the inter-organelle trafficking of ceramide in response to the perturbation of cellular sphingomyelin and/or other sphingolipids.
    Journal of Biological Chemistry 02/2014; 289(15). DOI:10.1074/jbc.M113.528380 · 4.57 Impact Factor
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    Toshiyuki Yamaji · Kentaro Hanada
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    ABSTRACT: Sphingolipids are essential components in eukaryotes and have various cellular functions. Recent developments in genome-editing technologies have facilitated gene disruption in various organisms and cell lines. We here show the disruption of various sphingolipid metabolic genes in human cervical carcinoma HeLa cells by using transcription activator-like effector nucleases (TALENs). A TALEN pair targeting the human CERT gene (alternative name COL4A3BP) encoding a ceramide transport protein induced a loss-of-function phenotype in more than 60% of HeLa cells even though the cell line has a pseudo-triploid karyotype. We have isolated several loss-of-function mutant clones for CERT, UGCG (encoding glucosylceramide synthase), and B4GalT5 (encoding the major lactosylceramide synthase), and also a CERT/UGCG double-deficient clone. Characterization of these clones supported previous proposals that CERT primarily contributes to the synthesis of SM but not GlcCer, and that B4GalT5 is the major LacCer synthase. These newly established sphingolipid-deficient HeLa cell mutants together with our previously established stable transfectants provide a 'sphingolipid-modified HeLa cell panel,' which will be useful to elucidate the functions of various sphingolipid species against essentially the same genomic background.
    PLoS ONE 02/2014; 9(2):e88124. DOI:10.1371/journal.pone.0088124 · 3.23 Impact Factor
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    ABSTRACT: Viral genetic diversity within infected cells or tissues, called viral quasispecies, has been mostly studied for RNA viruses, but has also been described among DNA viruses, including human papillomavirus type 16 (HPV16) present in cervical precancerous lesions. However, the extent of HPV genetic variation in cervical specimens, and its involvement in HPV-induced carcinogenesis, remains unclear. Here, we employ deep sequencing to comprehensively analyze genetic variation in the HPV16 genome isolated from individual clinical specimens. Through overlapping full-circle PCR, approximately 8-kb DNA fragments covering the whole HPV16 genome were amplified from HPV16-positive cervical exfoliated cells collected from patients with either low-grade squamous intraepithelial lesion (LSIL) or invasive cervical cancer (ICC). Deep sequencing of the amplified HPV16 DNA enabled de novo assembly of the full-length HPV16 genome sequence for each of 7 specimens (5 LSIL and 2 ICC samples). Subsequent alignment of read sequences to the assembled HPV16 sequence revealed that 2 LSILs and 1 ICC contained nucleotide variations within E6, E1 and the non-coding region between E5 and L2 with mutation frequencies of 0.60% to 5.42%. In transient replication assays, a novel E1 mutant found in ICC, E1 Q381E, showed reduced ability to support HPV16 origin-dependent replication. In addition, partially deleted E2 genes were detected in 1 LSIL sample in a mixed state with the intact E2 gene. Thus, the methods used in this study provide a fundamental framework for investigating the influence of HPV somatic genetic variation on cervical carcinogenesis.
    PLoS ONE 11/2013; 8(11):e80583. DOI:10.1371/journal.pone.0080583 · 3.23 Impact Factor
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    ABSTRACT: Lipids synthesized at the endoplasmic reticulum (ER) are delivered to the Golgi by vesicular and non-vesicular pathways. ER-to-Golgi transport is critical for maintaining the different membrane lipid composition and identities of organelles. Despite their importance, mechanisms regulating transport remain elusive. Here we report that coat protein complex II (COPII) vesicle-mediated transport of ceramide from the ER to the Golgi requires the yeast oxysterol-binding protein homologs, Osh proteins, which have been implicated in lipid homeostasis. Because Osh proteins are not required to transport proteins to the Golgi, these results indicate a specific requirement for the Osh proteins in the transport of ceramide. In addition, we provide evidence that Osh proteins play a negative role in COPII vesicle biogenesis. Together, our data suggest that ceramide transport and sphingolipid levels between the ER and Golgi are maintained by two distinct functions of Osh proteins, which negatively regulate COPII vesicle formation and positively control the late stage, presumably fusion of ceramide-enriched vesicles with Golgi compartments.
    Journal of Cell Science 11/2013; 127(2). DOI:10.1242/jcs.132001 · 5.33 Impact Factor
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    ABSTRACT: Phosphoinositides function as fundamental signaling molecules and play roles in diverse cellular processes. Certain types of viruses may employ host cell phosphoinositide signaling systems to facilitate their replication cycles. Here we demonstrate that the β isoform of class II PI3K (PI3K-C2β) plays an indispensable role in hepatitis C virus (HCV) propagation in human hepatocellular carcinoma cells. Knockdown of PI3K-C2β abrogated HCV propagation in the cell. Using an HCV replicon system, we found that knockdown of PI3K-C2β substantially repressed the full-genome replication, while showing relatively small reductions in sub-genome replication, in which structural proteins including core protein were deleted. We also found that HCV core protein showed the binding activity towards D4-phosphorylated phosphoinositides and overlapped localization with phosphatidylinositol 3,4-bisphosphate in the cell. These results suggest that the phosphoinositide generated by PI3K-C2β plays an indispensable role in the HCV replication cycle through the binding to HCV core protein.
    Biochemical and Biophysical Research Communications 09/2013; 440(1). DOI:10.1016/j.bbrc.2013.09.048 · 2.28 Impact Factor
  • Kentaro Hanada
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    ABSTRACT: Life creates many varieties of lipids. The choline-containing sphingophospholipid sphingomyelin (SM) exists ubiquitously or widely in vertebrates and lower animals, but is absent or rare in bacteria, fungi, protists, and plants. In the biosynthesis of SM, ceramide, which is synthesized in the endoplasmic reticulum, is transported to the Golgi region by the ceramide transport protein CERT, probably in a non-vesicular manner, and is then converted to SM by SM synthase, which catalyzes the reaction of phosphocholine transfer from phosphatidylcholine (PtdCho) to ceramide. Recent advances in genomics and lipidomics indicate that the phylogenetic occurrence of CERT and its orthologs is nearly parallel to that of SM. Based on the chemistry of lipids together with evolutionary aspects of SM and CERT, several concepts are here proposed. SM may serve as a chemically inert and robust, but non-covalently interactive lipid class at the outer leaflet of the plasma membrane. The functional domains and peptidic motifs of CERT are separated by exon units, suggesting an exon-shuffling mechanism for the generation of an ancestral CERT gene. CERT may have co-evolved with SM to bypass a competing metabolic reaction at the bifurcated point in the anabolism of ceramide. Human CERT is identical to the splicing variant of human Goodpasture antigen-binding protein (GPBP) annotated as an extracellular non-canonical serine/threonine protein kinase. The relationship between CERT and GPBP has also been discussed from an evolutionary aspect. Moreover, using an analogy of "compatible (or osmoprotective) solutes" that can accumulate to very high concentrations in the cytosol without denaturing proteins, choline phospholipids such as PtdCho and SM may act as compatible phospholipids in biomembranes. This article is part of a Special Issue entitled New frontiers in sphingolipid biology.
    Biochimica et Biophysica Acta 07/2013; 1841(10). DOI:10.1016/j.bbalip.2013.06.006 · 4.66 Impact Factor
  • Ken'ichi Hagiwara · Hideyuki Hara · Kentaro Hanada
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    ABSTRACT: Transmissible spongiform encephalopathies (TSEs), or prion diseases, are fatal infectious neurodegenerative disorders. Their causative agents are prions which are composed of disease-associated forms of prion protein (PrP(Sc)). Naturally occurring cases of TSEs are found in several mammalian species including humans, sheep, goats, minks, cattle and deer. Prions are also experimentally transmissible to other mammals such as mice, hamsters and monkeys, but interspecies transmission is often inefficient due to the 'species-barrier'. Studies have suggested that the barrier is not simply determined by differences in amino acid sequences of cellular prion protein (PrP(C)) among animal species, but also by prion strains which are closely associated with conformational properties of PrP(Sc) aggregates. Although the conformational properties of PrP(Sc) remain largely unknown, recent investigation of local structures of PrP(C) and, in particular, structural modeling of PrP(Sc) aggregates have provided molecular insight into this field. In this review, we discuss the species-barrier phenomenon in terms of the protein science.
    Journal of Biochemistry 01/2013; 153(2). DOI:10.1093/jb/mvs148 · 3.07 Impact Factor

Publication Stats

4k Citations
504.53 Total Impact Points

Institutions

  • 1997–2015
    • National Institute of Infectious Diseases, Tokyo
      Edo, Tōkyō, Japan
  • 2010
    • The University of Tokyo
      Tōkyō, Japan
  • 2008
    • National Institute of Biomedical Innovation
      Ibaragi, Ōsaka, Japan
    • Karmanos Cancer Institute
      Detroit, Michigan, United States
  • 1998
    • Tokyo University of Science
      • Department of Pure and Applied Chemistry
      Edo, Tōkyō, Japan