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  • 1
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    Crystal structure of a membrane-embedded H+-translocating pyrophosphatase (2012)
    Nature Publishing Group (NPG)
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    Publication Date: 2012-03-30
    Description: H(+)-translocating pyrophosphatases (H(+)-PPases) are active proton transporters that establish a proton gradient across the endomembrane by means of pyrophosphate (PP(i)) hydrolysis. H(+)-PPases are found primarily as homodimers in the vacuolar membrane of plants and the plasma membrane of several protozoa and prokaryotes. The three-dimensional structure and detailed mechanisms underlying the enzymatic and proton translocation reactions of H(+)-PPases are unclear. Here we report the crystal structure of a Vigna radiata H(+)-PPase (VrH(+)-PPase) in complex with a non-hydrolysable substrate analogue, imidodiphosphate (IDP), at 2.35 A resolution. Each VrH(+)-PPase subunit consists of an integral membrane domain formed by 16 transmembrane helices. IDP is bound in the cytosolic region of each subunit and trapped by numerous charged residues and five Mg(2+) ions. A previously undescribed proton translocation pathway is formed by six core transmembrane helices. Proton pumping can be initialized by PP(i) hydrolysis, and H(+) is then transported into the vacuolar lumen through a pathway consisting of Arg 242, Asp 294, Lys 742 and Glu 301. We propose a working model of the mechanism for the coupling between proton pumping and PP(i) hydrolysis by H(+)-PPases.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Lin, Shih-Ming -- Tsai, Jia-Yin -- Hsiao, Chwan-Deng -- Huang, Yun-Tzu -- Chiu, Chen-Liang -- Liu, Mu-Hsuan -- Tung, Jung-Yu -- Liu, Tseng-Huang -- Pan, Rong-Long -- Sun, Yuh-Ju -- England -- Nature. 2012 Mar 28;484(7394):399-403. doi: 10.1038/nature10963.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Life Science and Institute of Bioinformatics and Structural Biology, College of Life Science, National Tsing Hua University, Hsinchu 30013, Taiwan.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/22456709" target="_blank"〉PubMed〈/a〉
    Keywords: Binding Sites ; Cell Membrane/metabolism ; Crystallography, X-Ray ; Cytosol/metabolism ; Diphosphonates/chemistry/metabolism ; Fabaceae/*enzymology ; Hydrolysis ; Inorganic Pyrophosphatase/*chemistry/*metabolism ; Magnesium/metabolism ; Membrane Proteins/*chemistry/metabolism ; Models, Molecular ; Protein Structure, Tertiary ; Protein Subunits/chemistry/metabolism ; Protons ; Static Electricity ; Vacuoles/metabolism
    Print ISSN: 0028-0836
    Electronic ISSN: 1476-4687
    Topics: Biology , Chemistry and Pharmacology , Medicine , Natural Sciences in General , Physics
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  • 2
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    Phosphorylation of MLL by ATR is required for execution of mammalian S-phase checkpoint (2010)
    Nature Publishing Group (NPG)
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    Publication Date: 2010-09-08
    Description: Cell cycle checkpoints are implemented to safeguard the genome, avoiding the accumulation of genetic errors. Checkpoint loss results in genomic instability and contributes to the evolution of cancer. Among G1-, S-, G2- and M-phase checkpoints, genetic studies indicate the role of an intact S-phase checkpoint in maintaining genome integrity. Although the basic framework of the S-phase checkpoint in multicellular organisms has been outlined, the mechanistic details remain to be elucidated. Human chromosome-11 band-q23 translocations disrupting the MLL gene lead to poor prognostic leukaemias. Here we assign MLL as a novel effector in the mammalian S-phase checkpoint network and identify checkpoint dysfunction as an underlying mechanism of MLL leukaemias. MLL is phosphorylated at serine 516 by ATR in response to genotoxic stress in the S phase, which disrupts its interaction with, and hence its degradation by, the SCF(Skp2) E3 ligase, leading to its accumulation. Stabilized MLL protein accumulates on chromatin, methylates histone H3 lysine 4 at late replication origins and inhibits the loading of CDC45 to delay DNA replication. Cells deficient in MLL showed radioresistant DNA synthesis and chromatid-type genomic abnormalities, indicative of S-phase checkpoint dysfunction. Reconstitution of Mll(-/-) (Mll also known as Mll1) mouse embryonic fibroblasts with wild-type but not S516A or DeltaSET mutant MLL rescues the S-phase checkpoint defects. Moreover, murine myeloid progenitor cells carrying an Mll-CBP knock-in allele that mimics human t(11;16) leukaemia show a severe radioresistant DNA synthesis phenotype. MLL fusions function as dominant negative mutants that abrogate the ATR-mediated phosphorylation/stabilization of wild-type MLL on damage to DNA, and thus compromise the S-phase checkpoint. Together, our results identify MLL as a key constituent of the mammalian DNA damage response pathway and show that deregulation of the S-phase checkpoint incurred by MLL translocations probably contributes to the pathogenesis of human MLL leukaemias.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2940944/" target="_blank"〉〈img src="https://static.pubmed.gov/portal/portal3rc.fcgi/4089621/img/3977009" border="0"〉〈/a〉   〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2940944/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Liu, Han -- Takeda, Shugaku -- Kumar, Rakesh -- Westergard, Todd D -- Brown, Eric J -- Pandita, Tej K -- Cheng, Emily H-Y -- Hsieh, James J-D -- CA119008/CA/NCI NIH HHS/ -- CA123232/CA/NCI NIH HHS/ -- CA129537/CA/NCI NIH HHS/ -- R01 CA119008/CA/NCI NIH HHS/ -- R01 CA119008-01/CA/NCI NIH HHS/ -- R01 CA119008-02/CA/NCI NIH HHS/ -- R01 CA119008-03/CA/NCI NIH HHS/ -- R01 CA119008-04/CA/NCI NIH HHS/ -- R01 CA119008-05/CA/NCI NIH HHS/ -- England -- Nature. 2010 Sep 16;467(7313):343-6. doi: 10.1038/nature09350. Epub 2010 Sep 5.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Medicine, Washington University School of Medicine, St Louis, Missouri 63110, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/20818375" target="_blank"〉PubMed〈/a〉
    Keywords: Alleles ; Animals ; Ataxia Telangiectasia Mutated Proteins ; Cell Cycle Proteins/*metabolism ; Cell Line ; Chromatin/metabolism ; DNA Damage ; DNA Replication/physiology ; Genes, Dominant/genetics ; Genomic Instability/physiology ; Histone-Lysine N-Methyltransferase ; Histones/chemistry/metabolism ; Humans ; Leukemia/genetics ; Lysine/metabolism ; Methylation ; Mice ; Myeloid Progenitor Cells/metabolism ; Myeloid-Lymphoid Leukemia Protein/chemistry/deficiency/genetics/*metabolism ; Phosphorylation ; Phosphoserine/metabolism ; Protein Binding ; Protein-Serine-Threonine Kinases/*metabolism ; S Phase/*physiology ; S-Phase Kinase-Associated Proteins/metabolism ; Signal Transduction ; Translocation, Genetic/genetics
    Print ISSN: 0028-0836
    Electronic ISSN: 1476-4687
    Topics: Biology , Chemistry and Pharmacology , Medicine , Natural Sciences in General , Physics
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  • 3
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    Fine-tuning of pre-balanced excitation and inhibition during auditory cortical development (2010)
    Nature Publishing Group (NPG)
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    Publication Date: 2010-06-19
    Description: Functional receptive fields of neurons in sensory cortices undergo progressive refinement during development. Such refinement may be attributed to the pruning of non-optimal excitatory inputs, reshaping of the excitatory tuning profile through modifying the strengths of individual inputs, or strengthening of cortical inhibition. These models have not been directly tested because of the technical difficulties in assaying the spatiotemporal patterns of functional synaptic inputs during development. Here we apply in vivo whole-cell voltage-clamp recordings to the recipient layer 4 neurons in the rat primary auditory cortex (A1) to determine the developmental changes in the frequency-intensity tonal receptive fields (TRFs) of their excitatory and inhibitory inputs. Surprisingly, we observe co-tuned excitation and inhibition immediately after the onset of hearing, suggesting that a tripartite thalamocortical circuit with relatively strong feedforward inhibition is formed independently of auditory experience. The frequency ranges of tone-driven excitatory and inhibitory inputs first expand within a few days of the onset of hearing and then persist into adulthood. The latter phase is accompanied by a sharpening of the excitatory but not inhibitory frequency tuning profile, which results in relatively broader inhibitory tuning in adult A1 neurons. Thus the development of cortical synaptic TRFs after the onset of hearing is marked by a slight breakdown of previously formed excitation-inhibition balance. Our results suggest that functional refinement of cortical TRFs does not require a selective pruning of inputs, but may depend more on a fine adjustment of excitatory input strengths.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2909826/" target="_blank"〉〈img src="https://static.pubmed.gov/portal/portal3rc.fcgi/4089621/img/3977009" border="0"〉〈/a〉   〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2909826/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Sun, Yujiao J -- Wu, Guangying K -- Liu, Bao-Hua -- Li, Pingyang -- Zhou, Mu -- Xiao, Zhongju -- Tao, Huizhong W -- Zhang, Li I -- EY018718/EY/NEI NIH HHS/ -- EY019049/EY/NEI NIH HHS/ -- R01 DC008983/DC/NIDCD NIH HHS/ -- R01 DC008983-01/DC/NIDCD NIH HHS/ -- R01 DC008983-02/DC/NIDCD NIH HHS/ -- R01 DC008983-03/DC/NIDCD NIH HHS/ -- R01 DC008983-04/DC/NIDCD NIH HHS/ -- R01 EY019049/EY/NEI NIH HHS/ -- R01 EY019049-02/EY/NEI NIH HHS/ -- R01DC008983/DC/NIDCD NIH HHS/ -- R03 DC006814/DC/NIDCD NIH HHS/ -- R03 DC006814-01A1/DC/NIDCD NIH HHS/ -- R03 DC006814-02/DC/NIDCD NIH HHS/ -- R03 DC006814-03/DC/NIDCD NIH HHS/ -- R21 DC008588/DC/NIDCD NIH HHS/ -- R21 DC008588-01/DC/NIDCD NIH HHS/ -- R21 DC008588-02/DC/NIDCD NIH HHS/ -- R21DC008588/DC/NIDCD NIH HHS/ -- UL1 RR025755/RR/NCRR NIH HHS/ -- England -- Nature. 2010 Jun 17;465(7300):927-31. doi: 10.1038/nature09079.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Zilkha Neurogenetic Institute, Keck School of Medicine, University of Southern California, Los Angeles, California 90089, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/20559386" target="_blank"〉PubMed〈/a〉
    Keywords: Acoustic Stimulation ; Animals ; Auditory Cortex/growth & development/*physiology ; Auditory Pathways/physiology ; Electrical Synapses/physiology ; Excitatory Postsynaptic Potentials/*physiology ; Hearing/physiology ; Neural Inhibition/*physiology ; Patch-Clamp Techniques ; Rats ; Rats, Sprague-Dawley ; Sensory Receptor Cells/*physiology ; Time Factors
    Print ISSN: 0028-0836
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    Topics: Biology , Chemistry and Pharmacology , Medicine , Natural Sciences in General , Physics
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  • 4
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    Functionally defective germline variants of sialic acid acetylesterase in autoimmunity (2010)
    Nature Publishing Group (NPG)
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    Publication Date: 2010-06-18
    Description: Sialic acid acetylesterase (SIAE) is an enzyme that negatively regulates B lymphocyte antigen receptor signalling and is required for the maintenance of immunological tolerance in mice. Heterozygous loss-of-function germline rare variants and a homozygous defective polymorphic variant of SIAE were identified in 24/923 subjects of European origin with relatively common autoimmune disorders and in 2/648 controls of European origin. All heterozygous loss-of-function SIAE mutations tested were capable of functioning in a dominant negative manner. A homozygous secretion-defective polymorphic variant of SIAE was catalytically active, lacked the ability to function in a dominant negative manner, and was seen in eight autoimmune subjects but in no control subjects. The odds ratio for inheriting defective SIAE alleles was 8.6 in all autoimmune subjects, 8.3 in subjects with rheumatoid arthritis, and 7.9 in subjects with type I diabetes. Functionally defective SIAE rare and polymorphic variants represent a strong genetic link to susceptibility in relatively common human autoimmune disorders.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2900412/" target="_blank"〉〈img src="https://static.pubmed.gov/portal/portal3rc.fcgi/4089621/img/3977009" border="0"〉〈/a〉   〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2900412/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Surolia, Ira -- Pirnie, Stephan P -- Chellappa, Vasant -- Taylor, Kendra N -- Cariappa, Annaiah -- Moya, Jesse -- Liu, Haoyuan -- Bell, Daphne W -- Driscoll, David R -- Diederichs, Sven -- Haider, Khaleda -- Netravali, Ilka -- Le, Sheila -- Elia, Roberto -- Dow, Ethan -- Lee, Annette -- Freudenberg, Jan -- De Jager, Philip L -- Chretien, Yves -- Varki, Ajit -- MacDonald, Marcy E -- Gillis, Tammy -- Behrens, Timothy W -- Bloch, Donald -- Collier, Deborah -- Korzenik, Joshua -- Podolsky, Daniel K -- Hafler, David -- Murali, Mandakolathur -- Sands, Bruce -- Stone, John H -- Gregersen, Peter K -- Pillai, Shiv -- AI 064930/AI/NIAID NIH HHS/ -- AI 068759/AI/NIAID NIH HHS/ -- AI 076505/AI/NIAID NIH HHS/ -- AR 022263/AR/NIAMS NIH HHS/ -- AR 044422/AR/NIAMS NIH HHS/ -- AR 058481/AR/NIAMS NIH HHS/ -- NS 32765/NS/NINDS NIH HHS/ -- P30 DK043351/DK/NIDDK NIH HHS/ -- R01 AI064930/AI/NIAID NIH HHS/ -- R01 AI064930-04/AI/NIAID NIH HHS/ -- R01 AI068759/AI/NIAID NIH HHS/ -- R01 AI068759-05/AI/NIAID NIH HHS/ -- R01 AI076505/AI/NIAID NIH HHS/ -- R01 AI076505-02/AI/NIAID NIH HHS/ -- R01 AR044422/AR/NIAMS NIH HHS/ -- R01 AR044422-13/AR/NIAMS NIH HHS/ -- RC1 AR058481/AR/NIAMS NIH HHS/ -- RC1 AR058481-01/AR/NIAMS NIH HHS/ -- England -- Nature. 2010 Jul 8;466(7303):243-7. doi: 10.1038/nature09115. Epub 2010 Jun 16.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Cancer Center, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts 02114, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/20555325" target="_blank"〉PubMed〈/a〉
    Keywords: Acetylation ; Acetylesterase/*genetics/metabolism/secretion ; Alleles ; Animals ; Antibodies, Antinuclear/blood ; Arthritis, Rheumatoid/enzymology/genetics ; Autoimmune Diseases/*enzymology/*genetics ; Autoimmunity/*genetics ; B-Lymphocytes/metabolism ; Biocatalysis ; Carboxylic Ester Hydrolases/*genetics/metabolism/secretion ; Case-Control Studies ; Cell Line ; Diabetes Mellitus, Type 1/enzymology/genetics ; Europe/ethnology ; Exons/genetics ; Genetic Predisposition to Disease/*genetics ; Germ-Line Mutation/*genetics ; Humans ; Mice ; N-Acetylneuraminic Acid/*metabolism ; Odds Ratio ; Polymorphism, Single Nucleotide/genetics ; Sample Size ; Sequence Analysis, DNA
    Print ISSN: 0028-0836
    Electronic ISSN: 1476-4687
    Topics: Biology , Chemistry and Pharmacology , Medicine , Natural Sciences in General , Physics
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  • 5
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    Precision microbiome reconstitution restores bile acid mediated resistance to Clostridium difficile (2014)
    Nature Publishing Group (NPG)
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    Publication Date: 2014-10-23
    Description: The gastrointestinal tracts of mammals are colonized by hundreds of microbial species that contribute to health, including colonization resistance against intestinal pathogens. Many antibiotics destroy intestinal microbial communities and increase susceptibility to intestinal pathogens. Among these, Clostridium difficile, a major cause of antibiotic-induced diarrhoea, greatly increases morbidity and mortality in hospitalized patients. Which intestinal bacteria provide resistance to C. difficile infection and their in vivo inhibitory mechanisms remain unclear. Here we correlate loss of specific bacterial taxa with development of infection, by treating mice with different antibiotics that result in distinct microbiota changes and lead to varied susceptibility to C. difficile. Mathematical modelling augmented by analyses of the microbiota of hospitalized patients identifies resistance-associated bacteria common to mice and humans. Using these platforms, we determine that Clostridium scindens, a bile acid 7alpha-dehydroxylating intestinal bacterium, is associated with resistance to C. difficile infection and, upon administration, enhances resistance to infection in a secondary bile acid dependent fashion. Using a workflow involving mouse models, clinical studies, metagenomic analyses, and mathematical modelling, we identify a probiotic candidate that corrects a clinically relevant microbiome deficiency. These findings have implications for the rational design of targeted antimicrobials as well as microbiome-based diagnostics and therapeutics for individuals at risk of C. difficile infection.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4354891/" target="_blank"〉〈img src="https://static.pubmed.gov/portal/portal3rc.fcgi/4089621/img/3977009" border="0"〉〈/a〉   〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4354891/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Buffie, Charlie G -- Bucci, Vanni -- Stein, Richard R -- McKenney, Peter T -- Ling, Lilan -- Gobourne, Asia -- No, Daniel -- Liu, Hui -- Kinnebrew, Melissa -- Viale, Agnes -- Littmann, Eric -- van den Brink, Marcel R M -- Jenq, Robert R -- Taur, Ying -- Sander, Chris -- Cross, Justin R -- Toussaint, Nora C -- Xavier, Joao B -- Pamer, Eric G -- AI95706/AI/NIAID NIH HHS/ -- DP2 OD008440/OD/NIH HHS/ -- DP2OD008440/OD/NIH HHS/ -- K23 AI095398/AI/NIAID NIH HHS/ -- P01 CA023766/CA/NCI NIH HHS/ -- P30 CA008748/CA/NCI NIH HHS/ -- R01 AI042135/AI/NIAID NIH HHS/ -- R01 AI095706/AI/NIAID NIH HHS/ -- R01 AI42135/AI/NIAID NIH HHS/ -- T32 CA009149/CA/NCI NIH HHS/ -- T32 GM007739/GM/NIGMS NIH HHS/ -- T32GM07739/GM/NIGMS NIH HHS/ -- U54 CA148967/CA/NCI NIH HHS/ -- England -- Nature. 2015 Jan 8;517(7533):205-8. doi: 10.1038/nature13828. Epub 2014 Oct 22.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉1] Infectious Diseases Service, Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, New York 10065, USA [2] Lucille Castori Center for Microbes, Inflammation and Cancer, Memorial Sloan Kettering Cancer Center, New York, New York 10065, USA. ; 1] Computational Biology Program, Sloan-Kettering Institute, New York, New York 10065, USA [2] Department of Biology, University of Massachusetts Dartmouth, North Dartmouth, Massachusetts 02747, USA. ; Computational Biology Program, Sloan-Kettering Institute, New York, New York 10065, USA. ; Lucille Castori Center for Microbes, Inflammation and Cancer, Memorial Sloan Kettering Cancer Center, New York, New York 10065, USA. ; Donald B. and Catherine C. Marron Cancer Metabolism Center, Sloan-Kettering Institute, New York, New York 10065, USA. ; Genomics Core Laboratory, Sloan-Kettering Institute, New York, New York 10065, USA. ; 1] Bone Marrow Transplant Service, Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, New York 10065, USA [2] Immunology Program, Sloan-Kettering Institute, New York, New York 10065, USA. ; Bone Marrow Transplant Service, Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, New York 10065, USA. ; 1] Lucille Castori Center for Microbes, Inflammation and Cancer, Memorial Sloan Kettering Cancer Center, New York, New York 10065, USA [2] Computational Biology Program, Sloan-Kettering Institute, New York, New York 10065, USA. ; 1] Infectious Diseases Service, Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, New York 10065, USA [2] Lucille Castori Center for Microbes, Inflammation and Cancer, Memorial Sloan Kettering Cancer Center, New York, New York 10065, USA [3] Immunology Program, Sloan-Kettering Institute, New York, New York 10065, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/25337874" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; Anti-Bacterial Agents/pharmacology ; Bile Acids and Salts/*metabolism ; Biological Evolution ; Clostridium/metabolism ; Clostridium difficile/drug effects/*physiology ; Colitis/metabolism/microbiology/prevention & control/therapy ; Disease Susceptibility/*microbiology ; Feces/microbiology ; Female ; Humans ; Intestines/drug effects/*metabolism/*microbiology ; Metagenome/genetics ; Mice ; Mice, Inbred C57BL ; Microbiota/drug effects/genetics/*physiology ; Symbiosis
    Print ISSN: 0028-0836
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    Topics: Biology , Chemistry and Pharmacology , Medicine , Natural Sciences in General , Physics
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  • 6
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    Patterns and rates of exonic de novo mutations in autism spectrum disorders (2012)
    Nature Publishing Group (NPG)
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    Publication Date: 2012-04-13
    Description: Autism spectrum disorders (ASD) are believed to have genetic and environmental origins, yet in only a modest fraction of individuals can specific causes be identified. To identify further genetic risk factors, here we assess the role of de novo mutations in ASD by sequencing the exomes of ASD cases and their parents (n = 175 trios). Fewer than half of the cases (46.3%) carry a missense or nonsense de novo variant, and the overall rate of mutation is only modestly higher than the expected rate. In contrast, the proteins encoded by genes that harboured de novo missense or nonsense mutations showed a higher degree of connectivity among themselves and to previous ASD genes as indexed by protein-protein interaction screens. The small increase in the rate of de novo events, when taken together with the protein interaction results, are consistent with an important but limited role for de novo point mutations in ASD, similar to that documented for de novo copy number variants. Genetic models incorporating these data indicate that most of the observed de novo events are unconnected to ASD; those that do confer risk are distributed across many genes and are incompletely penetrant (that is, not necessarily sufficient for disease). Our results support polygenic models in which spontaneous coding mutations in any of a large number of genes increases risk by 5- to 20-fold. Despite the challenge posed by such models, results from de novo events and a large parallel case-control study provide strong evidence in favour of CHD8 and KATNAL2 as genuine autism risk factors.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3613847/" target="_blank"〉〈img src="https://static.pubmed.gov/portal/portal3rc.fcgi/4089621/img/3977009" border="0"〉〈/a〉   〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3613847/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Neale, Benjamin M -- Kou, Yan -- Liu, Li -- Ma'ayan, Avi -- Samocha, Kaitlin E -- Sabo, Aniko -- Lin, Chiao-Feng -- Stevens, Christine -- Wang, Li-San -- Makarov, Vladimir -- Polak, Paz -- Yoon, Seungtai -- Maguire, Jared -- Crawford, Emily L -- Campbell, Nicholas G -- Geller, Evan T -- Valladares, Otto -- Schafer, Chad -- Liu, Han -- Zhao, Tuo -- Cai, Guiqing -- Lihm, Jayon -- Dannenfelser, Ruth -- Jabado, Omar -- Peralta, Zuleyma -- Nagaswamy, Uma -- Muzny, Donna -- Reid, Jeffrey G -- Newsham, Irene -- Wu, Yuanqing -- Lewis, Lora -- Han, Yi -- Voight, Benjamin F -- Lim, Elaine -- Rossin, Elizabeth -- Kirby, Andrew -- Flannick, Jason -- Fromer, Menachem -- Shakir, Khalid -- Fennell, Tim -- Garimella, Kiran -- Banks, Eric -- Poplin, Ryan -- Gabriel, Stacey -- DePristo, Mark -- Wimbish, Jack R -- Boone, Braden E -- Levy, Shawn E -- Betancur, Catalina -- Sunyaev, Shamil -- Boerwinkle, Eric -- Buxbaum, Joseph D -- Cook, Edwin H Jr -- Devlin, Bernie -- Gibbs, Richard A -- Roeder, Kathryn -- Schellenberg, Gerard D -- Sutcliffe, James S -- Daly, Mark J -- KL2 RR024977/RR/NCRR NIH HHS/ -- P30 HD015052/HD/NICHD NIH HHS/ -- P50 GM071558/GM/NIGMS NIH HHS/ -- P50 HD055751/HD/NICHD NIH HHS/ -- R01 MH057881/MH/NIMH NIH HHS/ -- R01 MH061009/MH/NIMH NIH HHS/ -- R01 MH089004/MH/NIMH NIH HHS/ -- R01 MH089025/MH/NIMH NIH HHS/ -- R01 MH089175/MH/NIMH NIH HHS/ -- R01 MH089208/MH/NIMH NIH HHS/ -- R01 MH089482/MH/NIMH NIH HHS/ -- R01MH084676/MH/NIMH NIH HHS/ -- R01MH089175/MH/NIMH NIH HHS/ -- R01MH089208/MH/NIMH NIH HHS/ -- T32 GM007753/GM/NIGMS NIH HHS/ -- TL1 RR024978/RR/NCRR NIH HHS/ -- U54 HG003067/HG/NHGRI NIH HHS/ -- U54 HG003273/HG/NHGRI NIH HHS/ -- UL1 RR024975/RR/NCRR NIH HHS/ -- England -- Nature. 2012 Apr 4;485(7397):242-5. doi: 10.1038/nature11011.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Analytic and Translational Genetics Unit, Department of Medicine, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts 02114, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/22495311" target="_blank"〉PubMed〈/a〉
    Keywords: Autistic Disorder/*genetics ; Case-Control Studies ; DNA-Binding Proteins/*genetics ; Exome/genetics ; Exons/*genetics ; Family Health ; Genetic Predisposition to Disease/*genetics ; Humans ; Models, Genetic ; Multifactorial Inheritance/genetics ; Mutation/*genetics ; Phenotype ; Poisson Distribution ; Protein Interaction Maps ; Transcription Factors/*genetics
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  • 7
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    BACH2 represses effector programs to stabilize T(reg)-mediated immune homeostasis (2013)
    Nature Publishing Group (NPG)
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    Publication Date: 2013-06-04
    Description: Through their functional diversification, distinct lineages of CD4(+) T cells can act to either drive or constrain immune-mediated pathology. Transcription factors are critical in the generation of cellular diversity, and negative regulators antagonistic to alternate fates often act in conjunction with positive regulators to stabilize lineage commitment. Genetic polymorphisms within a single locus encoding the transcription factor BACH2 are associated with numerous autoimmune and allergic diseases including asthma, Crohn's disease, coeliac disease, vitiligo, multiple sclerosis and type 1 diabetes. Although these associations point to a shared mechanism underlying susceptibility to diverse immune-mediated diseases, a function for BACH2 in the maintenance of immune homeostasis has not been established. Here, by studying mice in which the Bach2 gene is disrupted, we define BACH2 as a broad regulator of immune activation that stabilizes immunoregulatory capacity while repressing the differentiation programs of multiple effector lineages in CD4(+) T cells. BACH2 was required for efficient formation of regulatory (Treg) cells and consequently for suppression of lethal inflammation in a manner that was Treg-cell-dependent. Assessment of the genome-wide function of BACH2, however, revealed that it represses genes associated with effector cell differentiation. Consequently, its absence during Treg polarization resulted in inappropriate diversion to effector lineages. In addition, BACH2 constrained full effector differentiation within TH1, TH2 and TH17 cell lineages. These findings identify BACH2 as a key regulator of CD4(+) T-cell differentiation that prevents inflammatory disease by controlling the balance between tolerance and immunity.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3710737/" target="_blank"〉〈img src="https://static.pubmed.gov/portal/portal3rc.fcgi/4089621/img/3977009" border="0"〉〈/a〉   〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3710737/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Roychoudhuri, Rahul -- Hirahara, Kiyoshi -- Mousavi, Kambiz -- Clever, David -- Klebanoff, Christopher A -- Bonelli, Michael -- Sciume, Giuseppe -- Zare, Hossein -- Vahedi, Golnaz -- Dema, Barbara -- Yu, Zhiya -- Liu, Hui -- Takahashi, Hayato -- Rao, Mahadev -- Muranski, Pawel -- Crompton, Joseph G -- Punkosdy, George -- Bedognetti, Davide -- Wang, Ena -- Hoffmann, Victoria -- Rivera, Juan -- Marincola, Francesco M -- Nakamura, Atsushi -- Sartorelli, Vittorio -- Kanno, Yuka -- Gattinoni, Luca -- Muto, Akihiko -- Igarashi, Kazuhiko -- O'Shea, John J -- Restifo, Nicholas P -- Z01 BC011037-01/Intramural NIH HHS/ -- Z99 CA999999/Intramural NIH HHS/ -- ZIA BC011037-02/Intramural NIH HHS/ -- England -- Nature. 2013 Jun 27;498(7455):506-10. doi: 10.1038/nature12199. Epub 2013 Jun 2.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Center for Cancer Research, National Cancer Institute, National Institutes of Health (NIH), Bethesda, Maryland 20892, USA. roychoudhuri@mail.nih.gov〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/23728300" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; Autoimmunity/immunology ; Basic-Leucine Zipper Transcription Factors/deficiency/genetics/*metabolism ; CD4-Positive T-Lymphocytes/cytology/immunology/metabolism ; Cell Differentiation/genetics/immunology ; Female ; Forkhead Transcription Factors/genetics/metabolism ; Homeostasis/genetics/*immunology ; Humans ; Immune Tolerance/genetics/immunology ; Inflammation/genetics/immunology/mortality/pathology ; Mice ; Mice, Inbred C57BL ; Mice, Knockout ; T-Lymphocytes, Regulatory/cytology/drug effects/*immunology/metabolism ; Transforming Growth Factor beta/pharmacology
    Print ISSN: 0028-0836
    Electronic ISSN: 1476-4687
    Topics: Biology , Chemistry and Pharmacology , Medicine , Natural Sciences in General , Physics
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    Metabolites produced by commensal bacteria promote peripheral regulatory T-cell generation (2013)
    Nature Publishing Group (NPG)
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    Publication Date: 2013-11-15
    Description: Intestinal microbes provide multicellular hosts with nutrients and confer resistance to infection. The delicate balance between pro- and anti-inflammatory mechanisms, essential for gut immune homeostasis, is affected by the composition of the commensal microbial community. Regulatory T cells (Treg cells) expressing transcription factor Foxp3 have a key role in limiting inflammatory responses in the intestine. Although specific members of the commensal microbial community have been found to potentiate the generation of anti-inflammatory Treg or pro-inflammatory T helper 17 (TH17) cells, the molecular cues driving this process remain elusive. Considering the vital metabolic function afforded by commensal microorganisms, we reasoned that their metabolic by-products are sensed by cells of the immune system and affect the balance between pro- and anti-inflammatory cells. We tested this hypothesis by exploring the effect of microbial metabolites on the generation of anti-inflammatory Treg cells. We found that in mice a short-chain fatty acid (SCFA), butyrate, produced by commensal microorganisms during starch fermentation, facilitated extrathymic generation of Treg cells. A boost in Treg-cell numbers after provision of butyrate was due to potentiation of extrathymic differentiation of Treg cells, as the observed phenomenon was dependent on intronic enhancer CNS1 (conserved non-coding sequence 1), essential for extrathymic but dispensable for thymic Treg-cell differentiation. In addition to butyrate, de novo Treg-cell generation in the periphery was potentiated by propionate, another SCFA of microbial origin capable of histone deacetylase (HDAC) inhibition, but not acetate, which lacks this HDAC-inhibitory activity. Our results suggest that bacterial metabolites mediate communication between the commensal microbiota and the immune system, affecting the balance between pro- and anti-inflammatory mechanisms.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3869884/" target="_blank"〉〈img src="https://static.pubmed.gov/portal/portal3rc.fcgi/4089621/img/3977009" border="0"〉〈/a〉   〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3869884/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Arpaia, Nicholas -- Campbell, Clarissa -- Fan, Xiying -- Dikiy, Stanislav -- van der Veeken, Joris -- deRoos, Paul -- Liu, Hui -- Cross, Justin R -- Pfeffer, Klaus -- Coffer, Paul J -- Rudensky, Alexander Y -- P30 CA008748/CA/NCI NIH HHS/ -- R37 AI034206/AI/NIAID NIH HHS/ -- R37AI034206/AI/NIAID NIH HHS/ -- T32 AI007621/AI/NIAID NIH HHS/ -- T32 CA009149/CA/NCI NIH HHS/ -- T32A1007621/PHS HHS/ -- Howard Hughes Medical Institute/ -- England -- Nature. 2013 Dec 19;504(7480):451-5. doi: 10.1038/nature12726. Epub 2013 Nov 13.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉1] Howard Hughes Medical Institute and Ludwig Center at Memorial Sloan-Kettering Cancer Center, New York, New York 10065, USA [2] Immunology Program, Memorial Sloan-Kettering Cancer Center, New York, New York 10065, USA. ; Donald B. and Catherine C. Marron Cancer Metabolism Center, Memorial Sloan-Kettering Cancer Center, New York, New York 10065, USA. ; Institute of Medical Microbiology and Hospital Hygiene, Heinrich-Heine-University Duesseldorf, Duesseldorf 40225, Germany. ; 1] Howard Hughes Medical Institute and Ludwig Center at Memorial Sloan-Kettering Cancer Center, New York, New York 10065, USA [2] Immunology Program, Memorial Sloan-Kettering Cancer Center, New York, New York 10065, USA [3] Department of Cell Biology, University Medical Center Utrecht, 3584 CX Utrecht, The Netherlands.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/24226773" target="_blank"〉PubMed〈/a〉
    Keywords: Acetylation ; Animals ; Butyrates/*metabolism ; *Cell Differentiation ; Cytokines/metabolism ; Dendritic Cells/immunology/metabolism ; Enhancer Elements, Genetic/genetics ; Fermentation ; Forkhead Transcription Factors/genetics/metabolism ; Histone Deacetylases/metabolism ; Inflammation Mediators/metabolism ; Intestinal Mucosa/cytology/immunology/metabolism/microbiology ; Intestines/cytology/immunology/*metabolism/*microbiology ; Introns/genetics ; Lymphocyte Count ; Male ; Mice ; Mice, Inbred C57BL ; Starch/metabolism ; *Symbiosis ; T-Lymphocytes, Regulatory/*cytology/immunology/*metabolism
    Print ISSN: 0028-0836
    Electronic ISSN: 1476-4687
    Topics: Biology , Chemistry and Pharmacology , Medicine , Natural Sciences in General , Physics
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    Structural basis for hijacking CBF-beta and CUL5 E3 ligase complex by HIV-1 Vif (2014)
    Nature Publishing Group (NPG)
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    Publication Date: 2014-01-10
    Description: The human immunodeficiency virus (HIV)-1 protein Vif has a central role in the neutralization of host innate defences by hijacking cellular proteasomal degradation pathways to subvert the antiviral activity of host restriction factors; however, the underlying mechanism by which Vif achieves this remains unclear. Here we report a crystal structure of the Vif-CBF-beta-CUL5-ELOB-ELOC complex. The structure reveals that Vif, by means of two domains, organizes formation of the pentameric complex by interacting with CBF-beta, CUL5 and ELOC. The larger domain (alpha/beta domain) of Vif binds to the same side of CBF-beta as RUNX1, indicating that Vif and RUNX1 are exclusive for CBF-beta binding. Interactions of the smaller domain (alpha-domain) of Vif with ELOC and CUL5 are cooperative and mimic those of SOCS2 with the latter two proteins. A unique zinc-finger motif of Vif, which is located between the two Vif domains, makes no contacts with the other proteins but stabilizes the conformation of the alpha-domain, which may be important for Vif-CUL5 interaction. Together, our data reveal the structural basis for Vif hijacking of the CBF-beta and CUL5 E3 ligase complex, laying a foundation for rational design of novel anti-HIV drugs.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Guo, Yingying -- Dong, Liyong -- Qiu, Xiaolin -- Wang, Yishu -- Zhang, Bailing -- Liu, Hongnan -- Yu, You -- Zang, Yi -- Yang, Maojun -- Huang, Zhiwei -- England -- Nature. 2014 Jan 9;505(7482):229-33. doi: 10.1038/nature12884.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉1] School of Life Science and Technology, Harbin Institute of Technology, Harbin 150080, China [2]. ; School of Life Science and Technology, Harbin Institute of Technology, Harbin 150080, China. ; MOE Key Laboratory of Protein Sciences, Tsinghua-Peking Center for Life Sciences, School of Life Sciences, Tsinghua University, Beijing 100084, China.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/24402281" target="_blank"〉PubMed〈/a〉
    Keywords: Amino Acid Sequence ; Core Binding Factor Alpha 2 Subunit/metabolism ; Core Binding Factor beta Subunit/*chemistry/*metabolism ; Crystallography, X-Ray ; Cullin Proteins/*chemistry/*metabolism ; Humans ; Models, Molecular ; Molecular Sequence Data ; Multiprotein Complexes/chemistry/metabolism ; Protein Binding ; Protein Stability ; Protein Structure, Tertiary ; Suppressor of Cytokine Signaling Proteins ; Transcription Factors/chemistry/metabolism ; vif Gene Products, Human Immunodeficiency Virus/*chemistry/*metabolism
    Print ISSN: 0028-0836
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    Topics: Biology , Chemistry and Pharmacology , Medicine , Natural Sciences in General , Physics
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    Recapitulation of premature ageing with iPSCs from Hutchinson-Gilford progeria syndrome (2011)
    Nature Publishing Group (NPG)
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    Publication Date: 2011-02-25
    Description: Hutchinson-Gilford progeria syndrome (HGPS) is a rare and fatal human premature ageing disease, characterized by premature arteriosclerosis and degeneration of vascular smooth muscle cells (SMCs). HGPS is caused by a single point mutation in the lamin A (LMNA) gene, resulting in the generation of progerin, a truncated splicing mutant of lamin A. Accumulation of progerin leads to various ageing-associated nuclear defects including disorganization of nuclear lamina and loss of heterochromatin. Here we report the generation of induced pluripotent stem cells (iPSCs) from fibroblasts obtained from patients with HGPS. HGPS-iPSCs show absence of progerin, and more importantly, lack the nuclear envelope and epigenetic alterations normally associated with premature ageing. Upon differentiation of HGPS-iPSCs, progerin and its ageing-associated phenotypic consequences are restored. Specifically, directed differentiation of HGPS-iPSCs to SMCs leads to the appearance of premature senescence phenotypes associated with vascular ageing. Additionally, our studies identify DNA-dependent protein kinase catalytic subunit (DNAPKcs, also known as PRKDC) as a downstream target of progerin. The absence of nuclear DNAPK holoenzyme correlates with premature as well as physiological ageing. Because progerin also accumulates during physiological ageing, our results provide an in vitro iPSC-based model to study the pathogenesis of human premature and physiological vascular ageing.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3088088/" target="_blank"〉〈img src="https://static.pubmed.gov/portal/portal3rc.fcgi/4089621/img/3977009" border="0"〉〈/a〉   〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3088088/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Liu, Guang-Hui -- Barkho, Basam Z -- Ruiz, Sergio -- Diep, Dinh -- Qu, Jing -- Yang, Sheng-Lian -- Panopoulos, Athanasia D -- Suzuki, Keiichiro -- Kurian, Leo -- Walsh, Christopher -- Thompson, James -- Boue, Stephanie -- Fung, Ho Lim -- Sancho-Martinez, Ignacio -- Zhang, Kun -- Yates, John 3rd -- Izpisua Belmonte, Juan Carlos -- P41 RR011823/RR/NCRR NIH HHS/ -- R01 DA025779/DA/NIDA NIH HHS/ -- R01 DA025779-01/DA/NIDA NIH HHS/ -- R01-DA025779/DA/NIDA NIH HHS/ -- T32 CA009370/CA/NCI NIH HHS/ -- T32 CA009370-25A1/CA/NCI NIH HHS/ -- England -- Nature. 2011 Apr 14;472(7342):221-5. doi: 10.1038/nature09879. Epub 2011 Feb 23.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Gene Expression Laboratory, Salk Institute for Biological Studies, 10010 North Torrey Pines Road, La Jolla, California 92037, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/21346760" target="_blank"〉PubMed〈/a〉
    Keywords: Aging/metabolism/pathology/physiology ; Aging, Premature/genetics/pathology/physiopathology ; Calcium-Binding Proteins/analysis ; Cell Aging ; Cell Differentiation ; Cell Line ; Cellular Reprogramming ; DNA-Activated Protein Kinase/metabolism ; Epigenesis, Genetic ; Fibroblasts/pathology ; Holoenzymes/metabolism ; Humans ; Induced Pluripotent Stem Cells/metabolism/*pathology ; Lamin Type A ; Microfilament Proteins/analysis ; Models, Biological ; Muscle, Smooth, Vascular/pathology ; Nuclear Envelope/pathology ; Nuclear Proteins/analysis/genetics/metabolism ; Phenotype ; Progeria/genetics/pathology/physiopathology ; Protein Precursors/analysis/genetics/metabolism ; Substrate Specificity
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    Electronic ISSN: 1476-4687
    Topics: Biology , Chemistry and Pharmacology , Medicine , Natural Sciences in General , Physics
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