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The stepwise assembly of the neonatal virome is modulated by breastfeeding 期刊论文
NATURE, 2020
作者:  Medina, Christopher B.;  Mehrotra, Parul;  Arandjelovic, Sanja;  Perrys, Justin S. A.;  Guo, Yizhan;  Morioka, Sho;  Barron, Brady;  Walk, Scott F.;  Ghesquiere, Bart;  Lorenz, Ulrike;  Krupnick, Alexander S.;  Ravichandran, Kodi S.
收藏  |  浏览/下载:36/0  |  提交时间:2020/07/03

The infant gut is colonized first by temperate bacteriophages induced from pioneer bacteria and later by viruses that replicate in human cells, the populations of which are modulated by breastfeeding.


The gut of healthy human neonates is usually devoid of viruses at birth, but quickly becomes colonized, which-in some cases-leads to gastrointestinal disorders(1-4). Here we show that the assembly of the viral community in neonates takes place in distinct steps. Fluorescent staining of virus-like particles purified from infant meconium or early stool samples shows few or no particles, but by one month of life particle numbers increase to 10(9) per gram, and these numbers seem to persist throughout life(5-7). We investigated the origin of these viral populations using shotgun metagenomic sequencing of virus-enriched preparations and whole microbial communities, followed by targeted microbiological analyses. Results indicate that, early after birth, pioneer bacteria colonize the infant gut and by one month prophages induced from these bacteria provide the predominant population of virus-like particles. By four months of life, identifiable viruses that replicate in human cells become more prominent. Multiple human viruses were more abundant in stool samples from babies who were exclusively fed on formula milk compared with those fed partially or fully on breast milk, paralleling reports that breast milk can be protective against viral infections(8-10). Bacteriophage populations also differed depending on whether or not the infant was breastfed. We show that the colonization of the infant gut is stepwise, first mainly by temperate bacteriophages induced from pioneer bacteria, and later by viruses that replicate in human cells  this second phase is modulated by breastfeeding.


  
Structure and mechanism of the ER-based glucosyltransferase ALG6 期刊论文
NATURE, 2020, 579 (7799) : 443-+
作者:  van Veen, Sarah;  Martin, Shaun;  Van den Haute, Chris;  Benoy, Veronick;  Lyons, Joseph;  Vanhoutte, Roeland;  Kahler, Jan Pascal;  Decuypere, Jean-Paul;  Gelders, Geraldine;  Lambie, Eric;  Zielich, Jeffrey;  Swinnen, Johannes V.;  Annaert, Wim;  Agostinis, Patrizia;  Ghesquiere, Bart;  Verhelst, Steven;  Baekelandt, Veerle;  Eggermont, Jan;  Vangheluwe, Peter
收藏  |  浏览/下载:13/0  |  提交时间:2020/07/03

Analyses reveal a previously undescribed transmembrane protein fold in the endoplasmic reticulum-based glucosyltransferase ALG6 and provide a structural basis for understanding the glucose transfer mechanism.


In eukaryotic protein N-glycosylation, a series of glycosyltransferases catalyse the biosynthesis of a dolichylpyrophosphate-linked oligosaccharide before its transfer onto acceptor proteins(1). The final seven steps occur in the lumen of the endoplasmic reticulum (ER) and require dolichylphosphate-activated mannose and glucose as donor substrates(2). The responsible enzymes-ALG3, ALG9, ALG12, ALG6, ALG8 and ALG10-are glycosyltransferases of the C-superfamily (GT-Cs), which are loosely defined as containing membrane-spanning helices and processing an isoprenoid-linked carbohydrate donor substrate(3,4). Here we present the cryo-electron microscopy structure of yeast ALG6 at 3.0 angstrom resolution, which reveals a previously undescribed transmembrane protein fold. Comparison with reported GT-C structures suggests that GT-C enzymes contain a modular architecture with a conserved module and a variable module, each with distinct functional roles. We used synthetic analogues of dolichylphosphate-linked and dolichylpyrophosphate-linked sugars and enzymatic glycan extension to generate donor and acceptor substrates using purified enzymes of the ALG pathway to recapitulate the activity of ALG6 in vitro. A second cryo-electron microscopy structure of ALG6 bound to an analogue of dolichylphosphate-glucose at 3.9 angstrom resolution revealed the active site of the enzyme. Functional analysis of ALG6 variants identified a catalytic aspartate residue that probably acts as a general base. This residue is conserved in the GT-C superfamily. Our results define the architecture of ER-luminal GT-C enzymes and provide a structural basis for understanding their catalytic mechanisms.


  
The role of fatty acid beta-oxidation in lymphangiogenesis 期刊论文
NATURE, 2017, 542 (7639) : 49-+
作者:  Wong, Brian W.;  Wang, Xingwu;  Zecchin, Annalisa;  Thienpont, Bernard;  Cornelissen, Ivo;  Kalucka, Joanna;  Garcia-Caballero, Melissa;  Missiaen, Rindert;  Huang, Hongling;  Burning, Ulrike;  Blacher, Silvia;  Vinckier, Stefan;  Goveia, Jermaine;  Knobloch, Marlen;  Zhao, Hui;  Dierkes, Cathrin;  Shi, Chenyan;  Haegerling, Rene;  Moral-Darde, Veronica;  Wyns, Sabine;  Lippens, Martin;  Jessberger, Sebastian;  Fendt, Sarah-Maria;  Luttun, Aernout;  Noel, Agnes;  Kiefer, Friedemann;  Ghesquiere, Bart;  Moons, Lieve;  Schoonjans, Luc;  Dewerchin, Mieke;  Eelen, Guy;  Lambrechts, Diether;  Carmeliet, Peter
收藏  |  浏览/下载:7/0  |  提交时间:2019/04/09