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https://www.readbyqxmd.com/read/28814507/systematic-gene-tagging-using-crispr-cas9-in-human-stem-cells-to-illuminate-cell-organization
#1
Brock Roberts, Amanda Haupt, Andrew Tucker, Tanya Grancharova, Joy Arakaki, Margaret A Fuqua, Angelique Nelson, Caroline Hookway, Susan A Ludmann, Irina A Mueller, Ruian Yang, Alan R Horwitz, Susanne M Rafelski, Ruwanthi N Gunawardane
We present a CRISPR/Cas9 genome editing strategy to systematically tag endogenous proteins with fluorescent tags in human induced pluripotent stem cells. To date we have generated multiple human iPSC lines with monoallelic GFP tags labeling 10 proteins representing major cellular structures. The tagged proteins include alpha tubulin, beta actin, desmoplakin, fibrillarin, nuclear lamin B1, non-muscle myosin heavy chain IIB, paxillin, Sec61 beta, tight junction protein ZO1, and Tom20. Our genome editing methodology using Cas9/crRNA ribonuclear protein and donor plasmid co-electroporation, followed by fluorescence-based enrichment of edited cells, typically resulted in <0...
August 16, 2017: Molecular Biology of the Cell
https://www.readbyqxmd.com/read/28782656/genetics-and-mechanisms-of-hepatic-cystogenesis
#2
REVIEW
L F M van de Laarschot, J P H Drenth
Polycystic liver disease (PLD) is a heterogeneous genetic condition. PKD1 and PKD2 germline mutations are found in patients with autosomal dominant polycystic kidney disease (ADPKD). Autosomal dominant polycystic liver disease (ADPLD) is associated with germline mutations in PRKCSH, SEC63, LRP5, and recently ALG8, and SEC61. GANAB mutations are found in both patient groups. Loss of heterozygosity of PLD-genes in cyst epithelium contributes to the development of hepatic cysts. A genetic interaction network is implied in hepatic cystogenesis that connects the endoplasmic glycoprotein control mechanisms and polycystin expression and localization...
August 4, 2017: Biochimica et Biophysica Acta
https://www.readbyqxmd.com/read/28782633/plasma-cell-deficiency-in-humans-with-heterozygous-mutations-in-sec61a1
#3
Desirée Schubert, Marie-Christine Klein, Sarah Hassdenteufel, Andrés Caballero-Oteyza, Linlin Yang, Michele Proietti, Alla Bulashevska, Janine Kemming, Johannes Kühn, Sandra Winzer, Stephan Rusch, Manfred Fliegauf, Alejandro A Schäffer, Stefan Pfeffer, Roger Geiger, Adolfo Cavalié, Hongzhi Cao, Fang Yang, Yong Li, Marta Rizzi, Hermann Eibel, Robin Kobbe, Amy L Marks, Brian P Peppers, Robert W Hostoffer, Jennifer M Puck, Richard Zimmermann, Bodo Grimbacher
BACKGROUND: Primary antibody deficiencies (PAD) are the most frequent primary immunodeficiencies in humans. The genetic causes for PADs are largely unknown. Sec61 translocon alpha 1 subunit (SEC61A1) is the major subunit of the Sec61 complex, which is the main polypeptide-conducting channel in the endoplasmic reticulum (ER) membrane. SEC61A1 is a target gene of XBP1s and strongly induced during plasma cell differentiation. OBJECTIVE: Characterization of a novel genetic defect and its pathological mechanism in eleven patients from two unrelated families with PAD...
August 3, 2017: Journal of Allergy and Clinical Immunology
https://www.readbyqxmd.com/read/28679634/sec61-blockade-by-mycolactone-inhibits-antigen-cross-presentation-independently-of-endosome-to-cytosol-export
#4
Jeff E Grotzke, Patrycja Kozik, Jean-David Morel, Francis Impens, Natalia Pietrosemoli, Peter Cresswell, Sebastian Amigorena, Caroline Demangel
Although antigen cross-presentation in dendritic cells (DCs) is critical to the initiation of most cytotoxic immune responses, the intracellular mechanisms and traffic pathways involved are still unclear. One of the most critical steps in this process, the export of internalized antigen to the cytosol, has been suggested to be mediated by Sec61. Sec61 is the channel that translocates signal peptide-bearing nascent polypeptides into the endoplasmic reticulum (ER), and it was also proposed to mediate protein retrotranslocation during ER-associated degradation (a process called ERAD)...
July 18, 2017: Proceedings of the National Academy of Sciences of the United States of America
https://www.readbyqxmd.com/read/28564553/structural-and-mechanistic-insights-into-protein-translocation
#5
Tom A Rapoport, Long Li, Eunyong Park
Many proteins are translocated across the endoplasmic reticulum (ER) membrane in eukaryotes or the plasma membrane in prokaryotes. These proteins use hydrophobic signal sequences or transmembrane (TM) segments to trigger their translocation through the protein-conducting Sec61/SecY channel. Substrates are first directed to the channel by cytosolic targeting factors, which use hydrophobic pockets to bind diverse signal and TM sequences. Subsequently, these hydrophobic sequences insert into the channel, docking into a groove on the outside of the lateral gate of the channel, where they also interact with lipids...
May 31, 2017: Annual Review of Cell and Developmental Biology
https://www.readbyqxmd.com/read/28504640/the-sec61-translocon-limits-ire1%C3%AE-signaling-during-the-unfolded-protein-response
#6
Arunkumar Sundaram, Rachel Plumb, Suhila Appathurai, Malaiyalam Mariappan
IRE1α is an endoplasmic reticulum (ER) localized endonuclease activated by misfolded proteins in the ER. Previously, we demonstrated that IRE1α forms a complex with the Sec61 translocon, to which its substrate XBP1u mRNA is recruited for cleavage during ER stress (Plumb et al., 2015). Here, we probe IRE1α complexes in cells with blue native PAGE immunoblotting. We find that IRE1α forms a hetero-oligomeric complex with the Sec61 translocon that is activated upon ER stress with little change in the complex...
May 15, 2017: ELife
https://www.readbyqxmd.com/read/28473450/zika-virus-induces-massive-cytoplasmic-vacuolization-and-paraptosis-like-death-in-infected-cells
#7
Blandine Monel, Alex A Compton, Timothée Bruel, Sonia Amraoui, Julien Burlaud-Gaillard, Nicolas Roy, Florence Guivel-Benhassine, Françoise Porrot, Pierre Génin, Laurent Meertens, Laura Sinigaglia, Nolwenn Jouvenet, Robert Weil, Nicoletta Casartelli, Caroline Demangel, Etienne Simon-Lorière, Arnaud Moris, Philippe Roingeard, Ali Amara, Olivier Schwartz
The cytopathic effects of Zika virus (ZIKV) are poorly characterized. Innate immunity controls ZIKV infection and disease in most infected patients through mechanisms that remain to be understood. Here, we studied the morphological cellular changes induced by ZIKV and addressed the role of interferon-induced transmembrane proteins (IFITM), a family of broad-spectrum antiviral factors, during viral replication. We report that ZIKV induces massive vacuolization followed by "implosive" cell death in human epithelial cells, primary skin fibroblasts and astrocytes, a phenomenon which is exacerbated when IFITM3 levels are low...
June 14, 2017: EMBO Journal
https://www.readbyqxmd.com/read/28454841/assisted-and-unassisted-protein-insertion-into-liposomes
#8
REVIEW
Andreas Kuhn, Maximilian Haase, Sebastian Leptihn
The insertion of newly synthesized membrane proteins is a well-regulated and fascinating process occurring in every living cell. Several translocases and insertases have been found in prokaryotic and eukaryotic cells, the Sec61 complex and the Get complex in the endoplasmic reticulum and the SecYEG complex and YidC in bacteria and archaea. In mitochondria, TOM and TIM complexes transport nuclear-encoded proteins, whereas the Oxa1 is required for the insertion of mitochondria-encoded membrane proteins. Related to the bacterial YidC and the mitochondrial Oxa1 are the Alb3 and Alb4 proteins in chloroplasts...
April 25, 2017: Biophysical Journal
https://www.readbyqxmd.com/read/28409218/transmembrane-helices-containing-a-charged-arginine-are-thermodynamically-stable
#9
Martin B Ulmschneider, Jakob P Ulmschneider, J Alfredo Freites, Gunnar von Heijne, Douglas J Tobias, Stephen H White
Hydrophobic amino acids are abundant in transmembrane (TM) helices of membrane proteins. Charged residues are sparse, apparently due to the unfavorable energetic cost of partitioning charges into nonpolar phases. Nevertheless, conserved arginine residues within TM helices regulate vital functions, such as ion channel voltage gating and integrin receptor inactivation. The energetic cost of arginine in various positions along hydrophobic helices has been controversial. Potential of mean force (PMF) calculations from atomistic molecular dynamics simulations predict very large energetic penalties, while in vitro experiments with Sec61 translocons indicate much smaller penalties, even for arginine in the center of hydrophobic TM helices...
April 13, 2017: European Biophysics Journal: EBJ
https://www.readbyqxmd.com/read/28365597/how-mycolactone-affects-sec61-it-s-complicated
#10
(no author information available yet)
No abstract text is available yet for this article.
April 1, 2017: Journal of Cell Science
https://www.readbyqxmd.com/read/28334946/mutations-affecting-the-transmembrane-domain-of-the-ldl-receptor-impact-of-charged-residues-on-the-membrane-insertion
#11
Thea Bismo Strøm, Jon K Laerdahl, Trond P Leren
Familial hypercholesterolemia (FH) is caused by mutations in the low density lipoprotein receptor (LDLR) gene. To study the impact of mutations affecting the hydrophobic transmembrane domain of the LDLR, each of the 22 amino acids of the transmembrane domain was individually mutated to arginine. The more centrally in the transmembrane domain an arginine was located, the lower amounts of the 120 kDa precursor LDLR in the endoplasmic reticulum were observed. This led to lower amounts of the 160 kDa mature LDLR on the cell surface...
May 1, 2017: Human Molecular Genetics
https://www.readbyqxmd.com/read/28286332/two-alternative-binding-mechanisms-connect-the-protein-translocation-sec71-sec72-complex-with-heat-shock-proteins
#12
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
https://www.readbyqxmd.com/read/28219954/mycolactone-reveals-the-substrate-driven-complexity-of-sec61-dependent-transmembrane-protein-biogenesis
#13
Michael McKenna, Rachel E Simmonds, Stephen High
Mycolactone is the exotoxin virulence factor produced by Mycobacterium ulcerans, the pathogen responsible for Buruli ulcer. The skin lesions and immunosuppression that are characteristic of this disease result from the action of mycolactone, which targets the Sec61 complex and inhibits the co-translational translocation of secretory proteins into the endoplasmic reticulum. In this study, we investigate the effect of mycolactone on the Sec61-dependent biogenesis of different classes of transmembrane protein (TMP)...
April 1, 2017: Journal of Cell Science
https://www.readbyqxmd.com/read/28218252/dissecting-the-molecular-organization-of-the-translocon-associated-protein-complex
#14
Stefan Pfeffer, Johanna Dudek, Miroslava Schaffer, Bobby G Ng, Sahradha Albert, Jürgen M Plitzko, Wolfgang Baumeister, Richard Zimmermann, Hudson H Freeze, Benjamin D Engel, Friedrich Förster
In eukaryotic cells, one-third of all proteins must be transported across or inserted into the endoplasmic reticulum (ER) membrane by the ER protein translocon. The translocon-associated protein (TRAP) complex is an integral component of the translocon, assisting the Sec61 protein-conducting channel by regulating signal sequence and transmembrane helix insertion in a substrate-dependent manner. Here we use cryo-electron tomography (CET) to study the structure of the native translocon in evolutionarily divergent organisms and disease-linked TRAP mutant fibroblasts from human patients...
February 20, 2017: Nature Communications
https://www.readbyqxmd.com/read/27974697/surrogate-in-vitro-activation-of-innate-immunity-synergizes-with-interleukin-7-to-unleash-rapid-antigen-driven-outgrowth-of-cd4-and-cd8-human-peripheral-blood-t-cells-naturally-recognizing-muc1-her2-neu-and-other-tumor-associated-antigens
#15
Latha B Pathangey, Dustin B McCurry, Sandra J Gendler, Ana L Dominguez, Jessica E Gorman, Girish Pathangey, Laurie A Mihalik, Yushe Dang, Mary L Disis, Peter A Cohen
Effective adoptive immunotherapy has proved elusive for many types of human cancer, often due to difficulties achieving robust expansion of natural tumor-specific T-cells from peripheral blood. We hypothesized that antigen-driven T-cell expansion might best be triggered in vitro by acute activation of innate immunity to mimic a life-threatening infection. Unfractionated peripheral blood mononuclear cells (PBMC) were subjected to a two-step culture, first synchronizing their exposure to exogenous antigens with aggressive surrogate activation of innate immunity, followed by γ-chain cytokine-modulated T-cell hyperexpansion...
February 14, 2017: Oncotarget
https://www.readbyqxmd.com/read/27936087/detection-of-placental-proteomes-at-different-uterine-positions-in-large-white-and-meishan-gilts-on-gestational-day-90
#16
Long Che, Mengmeng Xu, Zhenguo Yang, Shengyu Xu, Lianqiang Che, Yan Lin, Zhengfeng Fang, Bin Feng, Jian Li, Daiwen Chen, De Wu
Within-litter uniformity in pigs is a major factor affecting piglet survival and growth performance. We know that Meishan (MS) gilts have higher piglet survival rate than Large White (LW) gilts because their foetal weight is less varied. To understand the molecular basis for placental nutritional transport during the late stages of gestation in LW and MS, we employed the isobaric tags for relative and absolute quantification (iTRAQ) method to investigate alterations in the placental proteomes of LW and MS gilts on gestational day 90...
2016: PloS One
https://www.readbyqxmd.com/read/27932072/a-case-for-sec61-channel-involvement-in-erad
#17
REVIEW
Karin Römisch
Proteins that misfold in the endoplasmic reticulum (ER) need to be transported back to the cytosol for degradation by proteasomes, a process known as ER-associated degradation (ERAD). The first candidate discussed as a retrograde protein transport conduit was the Sec61 channel which is responsible for secretory protein transport into the ER during biogenesis. The Sec61 channel binds the proteasome 19S regulatory particle which can extract an ERAD substrate from the ER. Nevertheless its role as a general export channel has been dismissed, and Hrd1 and Der1 have been proposed as alternatives...
December 5, 2016: Trends in Biochemical Sciences
https://www.readbyqxmd.com/read/27927092/an-rnai-screen-for-genes-involved-in-nanoscale-protrusion-formation-on-corneal-lens-in-drosophila-melanogaster
#18
Ryunosuke Minami, Chiaki Sato, Yumi Yamahama, Hideo Kubo, Takahiko Hariyama, Ken-Ichi Kimura
The "moth-eye" structure, which is observed on the surface of corneal lens in several insects, supports anti-reflective and self-cleaning functions due to nanoscale protrusions known as corneal nipples. Although the morphology and function of the "moth-eye" structure, are relatively well studied, the mechanism of protrusion formation from cell-secreted substances is unknown. In Drosophila melanogaster, a compound eye consists of approximately 800 facets, the surface of which is formed by the corneal lens with nanoscale protrusions...
December 2016: Zoological Science
https://www.readbyqxmd.com/read/27909247/integration-of-transmembrane-domains-is-regulated-by-their-downstream-sequences
#19
Tina Junne, Martin Spiess
The Sec61 translocon catalyzes translocation of proteins into the endoplasmic reticulum and the lateral integration of transmembrane segments into the lipid bilayer. Integration is mediated by the hydrophobicity of a polypeptide segment consistent with thermodynamic equilibration between the translocon and the lipid membrane. Integration efficiency of a generic series of increasingly hydrophobic sequences (H-segments) was found to diverge significantly in different reporter constructs as a function of the ∼100 residues that are C-terminal to the H-segments...
January 15, 2017: Journal of Cell Science
https://www.readbyqxmd.com/read/27821549/mycolactone-subverts-immunity-by-selectively-blocking-the-sec61-translocon
#20
Ludivine Baron, Anja Onerva Paatero, Jean-David Morel, Francis Impens, Laure Guenin-Macé, Sarah Saint-Auret, Nicolas Blanchard, Rabea Dillmann, Fatoumata Niang, Sandra Pellegrini, Jack Taunton, Ville O Paavilainen, Caroline Demangel
Mycolactone, an immunosuppressive macrolide released by the human pathogen Mycobacterium ulcerans, was previously shown to impair Sec61-dependent protein translocation, but the underlying molecular mechanism was not identified. In this study, we show that mycolactone directly targets the α subunit of the Sec61 translocon to block the production of secreted and integral membrane proteins with high potency. We identify a single-amino acid mutation conferring resistance to mycolactone, which localizes its interaction site near the lumenal plug of Sec61α...
December 12, 2016: Journal of Experimental Medicine
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