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Fiorenza Fumagalli, Julia Noack, Timothy J Bergmann, Eduardo Cebollero, Giorgia Brambilla Pisoni, Elisa Fasana, Ilaria Fregno, Carmela Galli, Marisa Loi, Tatiana Soldà, Rocco D'Antuono, Andrea Raimondi, Martin Jung, Armin Melnyk, Stefan Schorr, Anne Schreiber, Luca Simonelli, Luca Varani, Caroline Wilson-Zbinden, Oliver Zerbe, Kay Hofmann, Matthias Peter, Manfredo Quadroni, Richard Zimmermann, Maurizio Molinari
No abstract text is available yet for this article.
December 23, 2016: Nature Cell Biology
Florian Bochen, Hana Adisurya, Silke Wemmert, Cornelia Lerner, Markus Greiner, Richard Zimmermann, Andrea Hasenfus, Mathias Wagner, Sigrun Smola, Thorsten Pfuhl, Alessandro Bozzato, Basel Al Kadah, Bernhard Schick, Maximilian Linxweiler
Chromosome 3q26 amplification represents a frequent alteration in head and neck squamous cell carcinomas (HNSCCs). Overexpression of 3q26 encoded genes SEC62 and SOX2 was detected in various cancers, including HNSCCs, indicating their potential function as oncogenes. In our study, we elucidated the function of SEC62 and SOX2 in HNSCC patients, with a main focus on their effect on lymphatic metastasis and patient survival. We analyzed SEC62 and SOX2 expression in tissue specimens from 65 HNSCC patients and 29 patients with cervical cancer of unknown primary (CUP); a higher SEC62 and lower SOX2 expression was observed in the lymph node metastases from HNSCC patients compared with the respective primary tumor...
December 16, 2016: Oncotarget
Sebastian Schuck
The endoplasmic reticulum (ER) is the largest membrane-bound organelle in cells, and its size needs to be carefully controlled. Downsizing the ER by autophagy is now shown to involve Sec62, a protein that also helps to build up the organelle. This link suggests a molecular switch for ER size control.
October 27, 2016: Nature Cell Biology
Fiorenza Fumagalli, Julia Noack, Timothy J Bergmann, Eduardo Cebollero, Giorgia Brambilla Pisoni, Elisa Fasana, Ilaria Fregno, Carmela Galli, Marisa Loi, Tatiana Soldà, Rocco D'Antuono, Andrea Raimondi, Martin Jung, Armin Melnyk, Stefan Schorr, Anne Schreiber, Luca Simonelli, Luca Varani, Caroline Wilson-Zbinden, Oliver Zerbe, Kay Hofmann, Matthias Peter, Manfredo Quadroni, Richard Zimmermann, Maurizio Molinari
The endoplasmic reticulum (ER) is a site of protein biogenesis in eukaryotic cells. Perturbing ER homeostasis activates stress programs collectively called the unfolded protein response (UPR). The UPR enhances production of ER-resident chaperones and enzymes to reduce the burden of misfolded proteins. On resolution of ER stress, ill-defined, selective autophagic programs remove excess ER components. Here we identify Sec62, a constituent of the translocon complex regulating protein import in the mammalian ER, as an ER-resident autophagy receptor...
November 2016: Nature Cell Biology
Maximilian Linxweiler, Florian Bochen, Bernhard Schick, Silke Wemmert, Basel Al Kadah, Markus Greiner, Andrea Hasenfus, Rainer-Maria Bohle, Ingolf Juhasz-Böss, Erich-Franz Solomayer, Zoltan Ferenc Takacs
BACKGROUND: Chromosome 3 amplification affecting the 3q26 region is a common genomic alteration in cervical cancer, typically marking the transition of precancerous intraepithelial lesions to an invasive phenotype. Though potential 3q encoded target genes of this amplification have been identified, a functional correlation of potential oncogenic function is still missing. In this study, we investigated copy number changes and the expression level of SEC62 encoded at 3q26.2 as a new potential 3q oncogene in dysplastic cervical lesions and analyzed its role in cervical cancer cell biology...
2016: BMC Cancer
Silke Wemmert, Yasmin Lindner, Johannes Linxweiler, Stefan Wagenpfeil, Rainer Bohle, Marcus Niewald, Bernhard Schick
Head and neck squamous cell carcinoma (HNSCC) is a malignancy with an increasing incidence. To aid with the selection of the most appropriate therapy, biomarkers have become a specific research focus. Sec62 is involved in endoplasmic reticulum stress tolerance and cell migration, and has been identified as a novel prognostic marker for non-small cell lung cancer. In addition, Sec62 may be a promising candidate in HNSCC. Pretreatment biopsies of 35 patients with locally advanced HNSCC, who were treated with definitive chemoradiation therapy without prior surgery, were examined for the expression of Sec62 protein, as well as the expression of epidermal growth factor receptor (EGFR), p16 and survivin proteins...
March 2016: Oncology Letters
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
Zhuangzhi Zhou, Zhiqian Pang, Guihua Li, Chunhua Lin, Jing Wang, Qiming Lv, Chaozu He, Lihuang Zhu
Pathogen-associated molecular pattern (PAMP)-triggered immunity (PTI) constitutes the first line of plant inducible immunity. As an important step of plant colonization, phytopathogens have to suppress PTI, and secreted effectors are therefore co-evolved and deployed. In this study, we characterized the function of MoSec62 of Magnaporthe oryzae, the causal agent of the destructive rice blast. MoSec62 encodes a homologue of Sec62p, a yeast endoplasmic reticulum (ER) membrane transporter for precursors of secretory proteins...
October 2016: Molecular Plant Pathology
Bhalchandra Jadhav, Michael McKenna, Nicholas Johnson, Stephen High, Irmgard Sinning, Martin R Pool
Two distinct pathways deliver secretory proteins to the Sec61 protein translocase in the endoplasmic reticulum membrane. The canonical pathway requires the signal recognition particle (SRP) and its cognate receptor (SR), and targets ribosome-associated proteins to the Sec translocase. The SRP-independent pathway requires the Sec translocase-associated ER membrane protein Sec62 and can be uncoupled from translation. Here we show that SR switches translocons to SRP-dependent translocation by displacing Sec62...
December 4, 2015: Nature Communications
Hui-Chen Guo, Ye Jin, Shi-Chong Han, Shi-Qi Sun, Yan-Quan Wei, Xian-Ji Liu, Xia Feng, Ding Xiang Liu, Xiang-Tao Liu
Stable isotope labeling with amino acids in cell culture (SILAC) was used to quantitatively study the host cell gene expression profile, in order to achieve an unbiased overview of the protein expression changes in BHK-21 cells infected with FMDV serotype Asia 1. The SILAC-based approach identified overall 2,141 proteins, 153 of which showed significant alteration in the expression level 6 h post FMDV infection (57 up-regulated and 96 down-regulated). Among these proteins, six cellular proteins, including three down-regulated (VPS28, PKR, EVI5) and three up-regulated (LYPLA1, SEC62 and DARs), were selected according to the significance of the changes and/or the relationship with PKR...
2015: PloS One
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
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
Sheldon G Watts, Justin J Crowder, Samuel Z Coffey, Eric M Rubenstein
Regulated protein degradation is crucial for virtually every cellular function. Much of what is known about the molecular mechanisms and genetic requirements for eukaryotic protein degradation was initially established in Saccharomyces cerevisiae. Classical analyses of protein degradation have relied on biochemical pulse-chase and cycloheximide-chase methodologies. While these techniques provide sensitive means for observing protein degradation, they are laborious, time-consuming, and low-throughput. These approaches are not amenable to rapid or large-scale screening for mutations that prevent protein degradation...
2015: Journal of Visualized Experiments: JoVE
Sung-jun Jung, Ji Eun Hani Kim, Johannes H Reithinger, Hyun Kim
The Sec62-Sec63 complex mediates post-translational translocation of a subset of primarily secretory proteins into the endoplasmic reticulum (ER) in yeast. Therefore, it has been thought that membrane proteins, which are mainly co-translationally targeted into the ER, are not handled by the Sec62-Sec63 translocon. By systematic analysis of single and multi-spanning membrane proteins with broad sequence context [with differing hydrophobicity, flanking charged residues and orientation of transmembrane (TM) segments], we show that mutations in the N-terminal cytosolic domain of yeast Sec62 impair its interaction with Sec63 and lead to defects in membrane insertion and translocation of the C-terminus of membrane proteins...
October 1, 2014: Journal of Cell Science
Maximilian Linxweiler, Stefan Schorr, Nico Schäuble, Martin Jung, Johannes Linxweiler, Frank Langer, Hans-Joachim Schäfers, Adolfo Cavalié, Richard Zimmermann, Markus Greiner
BACKGROUND: Tumor cells benefit from their ability to avoid apoptosis and invade other tissues. The endoplasmic reticulum (ER) membrane protein Sec62 is a key player in these processes. Sec62 is essential for cell migration and protects tumor cells against thapsigargin-induced ER stress, which are both linked to cytosolic Ca²⁺. SEC62 silencing leads to elevated cytosolic Ca²⁺ and increased ER Ca²⁺ leakage after thapsigargin treatment. Sec62 protein levels are significantly increased in different tumors, including prostate, lung and thyroid cancer...
2013: BMC Cancer
Nicholas Johnson, Sarah Haßdenteufel, Melanie Theis, Adrienne W Paton, James C Paton, Richard Zimmermann, Stephen High
The metazoan Sec61 translocon transports polypeptides into and across the membrane of the endoplasmic reticulum via two major routes, a well-established co-translational pathway and a post-translational alternative. We have used two model substrates to explore the elements of a secretory protein precursor that preferentially direct it towards a co- or post-translational pathway for ER translocation. Having first determined the capacity of precursors to enter ER derived microsomes post-translationally, we then exploited semi-permeabilized mammalian cells specifically depleted of key membrane components using siRNA to address their contribution to the membrane translocation process...
2013: PloS One
Daniel Hagerstrand, Alexander Tong, Steven E Schumacher, Nina Ilic, Rhine R Shen, Hiu Wing Cheung, Francisca Vazquez, Yashaswi Shrestha, So Young Kim, Andrew O Giacomelli, Joseph Rosenbluh, Anna C Schinzel, Nicole A Spardy, David A Barbie, Craig H Mermel, Barbara A Weir, Levi A Garraway, Pablo Tamayo, Jill P Mesirov, Rameen Beroukhim, William C Hahn
UNLABELLED: 3q26 is frequently amplified in several cancer types with a common amplified region containing 20 genes. To identify cancer driver genes in this region, we interrogated the function of each of these genes by loss- and gain-of-function genetic screens. Specifically, we found that TLOC1 (SEC62) was selectively required for the proliferation of cell lines with 3q26 amplification. Increased TLOC1 expression induced anchorage-independent growth, and a second 3q26 gene, SKIL (SNON), facilitated cell invasion in immortalized human mammary epithelial cells...
September 2013: Cancer Discovery
Regina Schweiger, Serena Schwenkert
The secretory system in eukaryotic organisms ensures targeting of proteins to their place of function after they entered the endoplasmic reticulum either co- or post-translationally. Thereby proteins are translocated through the Sec translocon into the endoplasmic reticulum. In the Arabidopsis genome homologs for the three major components of the Sec translocon, the central pore Sec61α and the auxiliary proteins Sec62 and Sec63 are present. Phylogenetic analyses show Sec61α to be the most conserved subunit within the Sec translocon whereas Sec62 and Sec63 show less homology but contain the same functional domains among all organisms...
August 2013: Plant Signaling & Behavior
Johannes H Reithinger, Ji Eun Hani Kim, Hyun Kim
Nascent chains are known to be targeted to the endoplasmic reticulum membrane either by a signal recognition particle (SRP)-dependent co-translational or by an SRP-independent post-translational translocation route depending on signal sequences. Using a set of model and cellular proteins carrying an N-terminal signal anchor sequence of controlled hydrophobicity and yeast mutant strains defective in SRP or Sec62 function, the hydrophobicity-dependent targeting efficiency and targeting pathway preference were systematically evaluated...
June 21, 2013: Journal of Biological Chemistry
Emmanuel Ampofo, Sabrina Welker, Martin Jung, Linda Müller, Markus Greiner, Richard Zimmermann, Mathias Montenarh
BACKGROUND: Protein kinase CK2 is a pleiotropic enzyme which is ubiquitously expressed in eukaryotic cells. Several years ago CK2 was found to be associated with the mammalian endoplasmic reticulum. So far nothing is known about the function of CK2 at the ER. METHODS: CK2 phosphorylation sites in the polypeptide chain of Sec63 were mapped using deletion mutants and a peptide library. Binding of Sec63 to CK2 and to Sec62 was analyzed by pull-down assays and by co-immunoprecipitation RESULTS: Sec63 was identified as a novel substrate and binding partner of protein kinase CK2...
April 2013: Biochimica et Biophysica Acta
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