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Whitney Besse, Ke Dong, Jungmin Choi, Sohan Punia, Sorin V Fedeles, Murim Choi, Anna-Rachel Gallagher, Emily B Huang, Ashima Gulati, James Knight, Shrikant Mane, Esa Tahvanainen, Pia Tahvanainen, Simone Sanna-Cherchi, Richard P Lifton, Terry Watnick, York P Pei, Vicente E Torres, Stefan Somlo
Dominantly inherited isolated polycystic liver disease (PCLD) consists of liver cysts that are radiologically and pathologically identical to those seen in autosomal dominant polycystic kidney disease, but without clinically relevant kidney cysts. The causative genes are known for fewer than 40% of PCLD index cases. Here, we have used whole exome sequencing in a discovery cohort of 102 unrelated patients who were excluded for mutations in the 2 most common PCLD genes, PRKCSH and SEC63, to identify heterozygous loss-of-function mutations in 3 additional genes, ALG8, GANAB, and SEC61B...
May 1, 2017: Journal of Clinical Investigation
Arati Tripathi, Elisabet C Mandon, Reid Gilmore, Tom A Rapoport
The biosynthesis of many eukaryotic proteins requires accurate targeting to and translocation across the endoplasmic reticulum membrane. Post-translational protein translocation in yeast requires both the Sec61 translocation channel, and a complex of four additional proteins: Sec63, Sec62, Sec71, and Sec72. The structure and function of these proteins are largely unknown. This pathway also requires the cytosolic Hsp70 protein Ssa1, but whether Ssa1 associates with the translocation machinery to target protein substrates to the membrane is unclear...
May 12, 2017: Journal of Biological Chemistry
Edgar S Wills, Wybrich R Cnossen, Joris A Veltman, Rob Woestenenk, Marloes Steehouwer, Jody Salomon, René H M Te Morsche, Meritxell Huch, Jayne Y Hehir-Kwa, Martijn J Banning, Rolph Pfundt, Ronald Roepman, Alexander Hoischen, Joost P H Drenth
Autosomal dominant polycystic liver disease (ADPLD) is caused by variants in PRKCSH, SEC63, and LRP5, whereas autosomal dominant polycystic kidney disease is caused by variants in PKD1 and PKD2. Liver cyst development in these disorders is explained by somatic loss-of-heterozygosity (LOH) of the wild-type allele in the developing cyst. We hypothesize that we can use this mechanism to identify novel disease genes that reside in LOH regions. In this study, we aim to map abnormal genomic regions using high-density SNP microarrays to find novel PLD genes...
December 2016: European Journal of Human Genetics: EJHG
Nicolas Tremblay, Martin Baril, Laurent Chatel-Chaix, Salwa Es-Saad, Alex Young Park, Robert K Koenekoop, Daniel Lamarre
Spliceosomal SNRNP200 is a Ski2-like RNA helicase that is associated with retinitis pigmentosa 33 (RP33). Here we found that SNRNP200 promotes viral RNA sensing and IRF3 activation through the ability of its amino-terminal Sec63 domain (Sec63-1) to bind RNA and to interact with TBK1. We show that SNRNP200 relocalizes into TBK1-containing cytoplasmic structures upon infection, in contrast to the RP33-associated S1087L mutant, which is also unable to rescue antiviral response of SNRNP200 knockdown cells. This functional rescue correlates with the Sec63-1-mediated binding of viral RNA...
July 2016: PLoS Pathogens
Binu Porath, Vladimir G Gainullin, Emilie Cornec-Le Gall, Elizabeth K Dillinger, Christina M Heyer, Katharina Hopp, Marie E Edwards, Charles D Madsen, Sarah R Mauritz, Carly J Banks, Saurabh Baheti, Bharathi Reddy, José Ignacio Herrero, Jesús M Bañales, Marie C Hogan, Velibor Tasic, Terry J Watnick, Arlene B Chapman, Cécile Vigneau, Frédéric Lavainne, Marie-Pierre Audrézet, Claude Ferec, Yannick Le Meur, Vicente E Torres, Peter C Harris
Autosomal-dominant polycystic kidney disease (ADPKD) is a common, progressive, adult-onset disease that is an important cause of end-stage renal disease (ESRD), which requires transplantation or dialysis. Mutations in PKD1 or PKD2 (∼85% and ∼15% of resolved cases, respectively) are the known causes of ADPKD. Extrarenal manifestations include an increased level of intracranial aneurysms and polycystic liver disease (PLD), which can be severe and associated with significant morbidity. Autosomal-dominant PLD (ADPLD) with no or very few renal cysts is a separate disorder caused by PRKCSH, SEC63, or LRP5 mutations...
June 2, 2016: American Journal of Human Genetics
Ronen Hope, Katarina Egarmina, Konstantin Voloshin, Hiba Waldman Ben-Asher, Shai Carmi, Dror Eliaz, Yaron Drori, Shulamit Michaeli
Under persistent ER stress, Trypanosoma brucei parasites induce the spliced leader silencing (SLS) pathway. In SLS, transcription of the SL RNA gene, the SL donor to all mRNAs, is extinguished, arresting trans-splicing and leading to programmed cell death (PCD). In this study, we investigated the transcriptome following silencing of SEC63, a factor essential for protein translocation across the ER membrane, and whose silencing induces SLS. The proteome of SEC63-silenced cells was analyzed with an emphasis on SLS-specific alterations in protein expression, and modifications that do not directly result from perturbations in trans-splicing...
October 2016: Molecular Microbiology
Richard Zimmermann
In mammalian cells, the endoplasmic reticulum (ER) plays a central role in biogenesis of secretory- and plasma membrane proteins as well as in cellular calcium (Ca(2+)) homeostasis. The protein biogenesis function involves an aqueous polypeptide conducting channel in the ER membrane, which is formed by the heterotrimeric Sec61 complex; the store- and receptor-controlled Ca(2+)- release function requires a steep ER to cytosol gradient, with more than 500 μM free Ca(2+) in the ER and 50 nM Ca(2+) in the cytosol...
May 2016: Journal of Clinical Immunology
Santharam S Katta, Jingjing Chen, Jennifer M Gardner, Jennifer M Friederichs, Sarah E Smith, Madelaine Gogol, Jay R Unruh, Brian D Slaughter, Sue L Jaspersen
In closed mitotic systems such as Saccharomyces cerevisiae, the nuclear envelope (NE) does not break down during mitosis, so microtubule-organizing centers such as the spindle-pole body (SPB) must be inserted into the NE to facilitate bipolar spindle formation and chromosome segregation. The mechanism of SPB insertion has been linked to NE insertion of nuclear pore complexes (NPCs) through a series of genetic and physical interactions between NPCs and SPB components. To identify new genes involved in SPB duplication and NE insertion, we carried out genome-wide screens for suppressors of deletion alleles of SPB components, including Mps3 and Mps2...
December 2015: Genetics
Wybrich R Cnossen, Jake S F Maurits, Jody Salomon, René H M Te Morsche, Esmé Waanders, Joost P H Drenth
BACKGROUND: Isolated polycystic liver disease (ADPLD) is an autosomal dominant Mendelian disorder. Heterozygous PRKCSH (where PRKCSH is protein kinase C substrate 80K-H (80 kDa protein, heavy chain; MIM*177060) mutations are the most frequent cause. Routine molecular testing using Sanger sequencing identifies pathogenic variants in the PRKCSH (15%) and SEC63 (where SEC63 is Saccharomyces cerevisiae homolog 63 (MIM*608648); 6%) genes, but about approximately 80% of patients meeting the clinical ADPLD criteria carry no PRKCSH or SEC63 mutation...
September 2016: Journal of Clinical Laboratory Analysis
Hossam Hassan, Xuefei Tian, Kazunori Inoue, Nathan Chai, Chang Liu, Keita Soda, Gilbert Moeckel, Alda Tufro, Ann-Hwee Lee, Stefan Somlo, Sorin Fedeles, Shuta Ishibe
Podocytes are terminally differentiated epithelial cells that reside along the glomerular filtration barrier. Evidence suggests that after podocyte injury, endoplasmic reticulum stress response is activated, but the molecular mechanisms involved are incompletely defined. In a mouse model, we confirmed that podocyte injury induces endoplasmic reticulum stress response and upregulated unfolded protein response pathways, which have been shown to mitigate damage by preventing the accumulation of misfolded proteins in the endoplasmic reticulum...
April 2016: Journal of the American Society of Nephrology: JASN
Stefan Schorr, Marie-Christine Klein, Igor Gamayun, Armin Melnyk, Martin Jung, Nico Schäuble, Qian Wang, Birgit Hemmis, Florian Bochen, Markus Greiner, Pavel Lampel, Sabine Katharina Urban, Sarah Hassdenteufel, Johanna Dudek, Xing-Zhen Chen, Richard Wagner, Adolfo Cavalié, Richard Zimmermann
In mammalian cells, signal peptide-dependent protein transport into the endoplasmic reticulum (ER) is mediated by a dynamic polypeptide-conducting channel, the heterotrimeric Sec61 complex. Previous work has characterized the Sec61 complex as a potential ER Ca(2+) leak channel in HeLa cells and identified ER lumenal molecular chaperone immunoglobulin heavy-chain-binding protein (BiP) as limiting Ca(2+) leakage via the open Sec61 channel by facilitating channel closing. This BiP activity involves binding of BiP to the ER lumenal loop 7 of Sec61α in the vicinity of tyrosine 344...
July 24, 2015: Journal of Biological Chemistry
Yanxin Zhao, Wei Tan, Wenhua Sheng, Xiaohong Li
BACKGROUND: This study aimed to explore the biomarkers of Alzheimer's disease (AD). METHODS: The microarray data of GSE16759 were from the expression profile samples of 4 parietal lobe tissues from patients with AD and 4 ones from age-matched control participants. The differentially expressed micro RNAs (miRNAs) and genes (DEGs) underwent hierarchical clustering and function analysis followed by target genes prediction. Finally, DEGs were mapped to the target genes to construct miRNA-regulated networks...
March 2016: American Journal of Alzheimer's Disease and Other Dementias
Eric M Davis, Jihye Kim, Bridget L Menasche, Jacob Sheppard, Xuedong Liu, Aik-Choon Tan, Jingshi Shen
Glycophosphatidylinositol-anchored proteins (GPI-APs) play essential roles in physiology, but their biogenesis and trafficking have not been systematically characterized. Here, we took advantage of the recently available haploid genetics approach to dissect GPI-AP pathways in human cells using prion protein (PrP) and CD59 as model molecules. Our screens recovered a large number of common and unexpectedly specialized factors in the GPI-AP pathways. PIGN, PGAP2, and PIGF, which encode GPI anchor-modifying enzymes, were selectively isolated in the CD59 screen, suggesting that GPI anchor composition significantly influences the biogenesis of GPI-APs in a substrate-dependent manner...
June 23, 2015: Cell Reports
Eva Absmeier, Leonie Rosenberger, Luise Apelt, Christian Becke, Karine F Santos, Ulrich Stelzl, Markus C Wahl
The spliceosomal RNA helicase Brr2 is required for the assembly of a catalytically active spliceosome on a messenger RNA precursor. Brr2 exhibits an unusual organization with tandem helicase units, each comprising dual RecA-like domains and a Sec63 homology unit, preceded by a more than 400-residue N-terminal helicase-associated region. Whereas recent crystal structures have provided insights into the molecular architecture and regulation of the Brr2 helicase region, little is known about the structural organization and function of its N-terminal part...
April 2015: Acta Crystallographica. Section D, Biological Crystallography
Sorin V Fedeles, Jae-Seon So, Amol Shrikhande, Seung Hun Lee, Anna-Rachel Gallagher, Christina E Barkauskas, Stefan Somlo, Ann-Hwee Lee
The HSP40 cochaperone SEC63 is associated with the SEC61 translocon complex in the ER. Mutations in the gene encoding SEC63 cause polycystic liver disease in humans; however, it is not clear how altered SEC63 influences disease manifestations. In mice, loss of SEC63 induces cyst formation both in liver and kidney as the result of reduced polycystin-1 (PC1). Here we report that inactivation of SEC63 induces an unfolded protein response (UPR) pathway that is protective against cyst formation. Specifically, using murine genetic models, we determined that SEC63 deficiency selectively activates the IRE1α-XBP1 branch of UPR and that SEC63 exists in a complex with PC1...
May 2015: Journal of Clinical Investigation
Brian J Conti, Prasanna K Devaraneni, Zhongying Yang, Larry L David, William R Skach
The ER Sec61 translocon is a large macromolecular machine responsible for partitioning secretory and membrane polypeptides into the lumen, cytosol, and lipid bilayer. Because the Sec61 protein-conducting channel has been isolated in multiple membrane-derived complexes, we determined how the nascent polypeptide modulates translocon component associations during defined cotranslational translocation events. The model substrate preprolactin (pPL) was isolated principally with Sec61αβγ upon membrane targeting, whereas higher-order complexes containing OST, TRAP, and TRAM were stabilized following substrate translocation...
April 16, 2015: Molecular Cell
Fani Papagiannouli, Ingrid Lohmann
A fundamental question in biology is how complex structures are maintained after their initial specification. We address this question by reviewing the role of the Hox gene Abd-B in Drosophila testis organogenesis, which proceeds through embryonic, larval and pupal stages to reach maturation in adult stages. The data presented in this review highlight a cell- and stage-specific function of Abd-B, since the mechanisms regulating stem cell niche positioning and architecture at different stages seem to be different despite the employment of similar factors...
2015: Computational and Structural Biotechnology Journal
Qilin Yu, Chang Jia, Yijie Dong, Bing Zhang, Chenpeng Xiao, Yulu Chen, Yuzhou Wang, Xiaoling Li, Lei Wang, Biao Zhang, Mingchun Li
Autophagy is a degradation process involved in pathogenicity of many pathogenic fungi. However, its roles in Candida albicans, the leading fungal pathogen in human beings, remain to be detailed. Most recently, we found that endoplasmic reticulum (ER) stress-inducing conditions led to transcriptional up-regulation of C. albicans autophagy-related (ATG) genes, implying a possible link between autophagy and ER stress response in this pathogen. Using a series of C. albicans ATG mutants and autophagy reporting systems, we found that both treatment of ER stress-related drugs and loss of the ER calcium pump Spf1 promoted autophagic flux of Atg8 and Lap41 (a homologue of Saccharomyces cerevisiae Ape1), indicating that these conditions induce autophagy...
August 2015: Fungal Genetics and Biology: FG & B
Olivier Cordin, Daniela Hahn, Ross Alexander, Amit Gautam, Cosmin Saveanu, J David Barrass, Jean D Beggs
RNA helicases are essential for virtually all cellular processes, however, their regulation is poorly understood. The activities of eight RNA helicases are required for pre-mRNA splicing. Amongst these, Brr2p is unusual in having two helicase modules, of which only the amino-terminal helicase domain appears to be catalytically active. Using genetic and biochemical approaches, we investigated interaction of the carboxy-terminal helicase module, in particular the carboxy-terminal Sec63-2 domain, with the splicing RNA helicase Prp16p...
December 16, 2014: Nucleic Acids Research
Ronen Hope, Efrat Ben-Mayor, Nehemya Friedman, Konstantin Voloshin, Dipul Biswas, Devorah Matas, Yaron Drori, Arthur Günzl, Shulamit Michaeli
The parasite Trypanosoma brucei is the causative agent of human African sleeping sickness. T. brucei genes are constitutively transcribed in polycistronic units that are processed by trans-splicing and polyadenylation. All mRNAs are trans-spliced to generate mRNAs with a common 5' exon derived from the spliced leader RNA (SL RNA). Persistent endoplasmic reticulum (ER) stress induces the spliced leader silencing (SLS) pathway, which inhibits trans-splicing by silencing SL RNA transcription, and correlates with increased programmed cell death...
September 2, 2014: Science Signaling
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