A5058249284- Endoplasmic Reticulum Stress and Disease
- Cellular transport and secretion
- RNA and protein synthesis mechanisms
- RNA regulation and disease
- Bacterial Genetics and Biotechnology
- Ubiquitin and proteasome pathways
- RNA modifications and cancer
- RNA Interference and Gene Delivery
- Gout, Hyperuricemia, Uric Acid
- Monoclonal and Polyclonal Antibodies Research
- Kidney Stones and Urolithiasis Treatments
- Ion channel regulation and function
- Protein Structure and Dynamics
- Calcium signaling and nucleotide metabolism
- Glycosylation and Glycoproteins Research
- Protein Degradation and Inhibitors
- Bacteriophages and microbial interactions
- Prion Diseases and Protein Misfolding
- Viral Infections and Vectors
- Pancreatic function and diabetes
- Inflammasome and immune disorders
- Toxin Mechanisms and Immunotoxins
- Transgenic Plants and Applications
- Pediatric Urology and Nephrology Studies
- Viral Infections and Immunology Research
Saarland University
2012-2023
Buck Institute for Research on Aging
2014-2019
Marin Community Foundation
2013-2015
Co-translational transport of polypeptides into the endoplasmic reticulum (ER) involves Sec61 channel and additional components such as ER lumenal Hsp70 BiP its membrane resident co-chaperone Sec63p in yeast. Here we investigated whether silencing SEC61A1 gene human cells affects co- posttranslational presecretory proteins integration tail-anchored proteins. While HeLa inhibited signal peptide-containing precursor semi-permeabilized cells, did not affect various types Furthermore,...
Abstract In mammalian cells, one-third of all polypeptides are transported into or across the ER membrane via Sec61 channel. While complex facilitates translocation with amino-terminal signal peptides (SP) transmembrane helices, Sec61-auxiliary translocon-associated protein (TRAP) supports only a subset precursors. To characterize determinants TRAP substrate specificity, we here systematically identify TRAP-dependent precursors by analyzing cellular abundance changes upon depletion using...
In mammalian cells, the endoplasmic reticulum (ER) plays a key role in protein biogenesis and calcium signalling. The heterotrimeric Sec61 complex ER membrane provides an aqueous pathway for transporting newly synthesized polypeptides into lumen may also allow leakage from cytosol. this study, planar lipid bilayer experiments demonstrated that is permeable to ions. We investigated whether silencing SEC61A1 gene affected ER. Silencing using two different siRNAs HeLa cells 96 hours had little...
Ectopic calcification is a driving force for variety of diseases, including kidney stones and atherosclerosis, but initiating factors remain largely unknown. Given its importance in seemingly divergent disease processes, identifying fundamental principal actors ectopic may have broad translational significance. Here we establish Drosophila melanogaster model by inhibiting xanthine dehydrogenase whose deficiency leads to humans dogs. Micro X-ray absorption near edge spectroscopy (μXANES)...
To fulfill its role in protein biogenesis, the endoplasmic reticulum (ER) depends on Hsp70-type molecular chaperone BiP, which requires a constant ATP supply. However, carrier that catalyzes uptake into ER was unknown. Here, we report our screen of gene expression datasets for member(s) family solute carriers are co-expressed with BiP and membrane proteins identifies SLC35B1 as potential candidate. Heterologous E. coli reveals is highly specific ADP acts antiport mode. Moreover, depletion...
In mammalian cells, one-third of all polypeptides are integrated into the membrane or translocated lumen endoplasmic reticulum (ER) via Sec61 channel. While complex facilitates ER import most precursor polypeptides, Sec61-associated Sec62/Sec63 supports in a substrate-specific manner. So far, mainly posttranslationally imported precursors and two cotranslationally ERj3 prion protein were found to depend on vitro. Therefore, we determined rules for engagement intact human cells using recently...
Summary Whilst the co-translational translocation of nascent proteins across mammalian endoplasmic reticulum (ER) is well defined, capacity this organelle for post-translational poorly delineated. Here we identify two human secretory protein precursors, apelin and statherin, as bona fide substrates ER membrane. Further studies, in combination with Hyalophora cecropia preprocecropin A (ppcecA), show that all three bind to TRC40 can utilise component their delivery membrane a well-established...
Elevated uric acid (UA) is a key risk factor for many disorders, including metabolic syndrome, gout and kidney stones. Despite frequent occurrence of these the genetic pathways influencing UA metabolism association with disease remain poorly understood. In humans, elevated levels resulted from loss urate oxidase (Uro) gene around 15 million years ago. Therefore, we established Drosophila melanogaster model reduced expression orthologous Uro to study pathogenesis arising UA. Reduced in...
BackgroundThe molecular cause of severe congenital neutropenia (SCN) is unknown in 30% to 50% patients. SEC61A1 encodes the α-subunit Sec61 complex, which governs endoplasmic reticulum protein transport and passive calcium leakage. Recently, mutations were reported be pathogenic common variable immunodeficiency glomerulocystic kidney disease.ObjectiveOur aim was expand spectrum SEC61A1-mediated disease include autosomal dominant SCN.MethodsWhole exome sequencing findings validated, compared...
Abstract BACKGROUND We previously reported that over‐expression of the SEC62 gene is a widespread phenomenon in prostate cancer. Since use endoplasmic reticulum (ER) stress‐inducing substances such as thapsigargin cancer therapy widely discussed literature, we investigated influence Sec62 protein content on cellular response to these drugs. METHODS Growth effects were analyzed by real‐time cell analysis and viability tests DU145‐cells representing an increased expression or PC3‐ LNCaP‐cells...
In human cells, one-third of all polypeptides enter the secretory pathway at endoplasmic reticulum (ER). The specificity and efficiency this process are guaranteed by targeting mRNAs and/or to ER membrane. Cytosolic SRP its receptor in membrane facilitate cotranslational most ribosome-nascent precursor polypeptide chain (RNC) complexes together with respective Sec61 complex Alternatively, fully synthesized targeted post-translationally either TRC, SND, or PEX19/3 pathway. Furthermore, there...
Abstract Patients suffering from immune‐mediated necrotizing myopathies (IMNM) harbor, the pathognomonic myositis‐specific auto‐antibodies anti‐SRP54 or ‐HMGCR, while about one third of them do not. Activation chaperone‐assisted autophagy was described as being part molecular etiology IMNM. Endoplasmic reticulum (ER)/sarcoplasmic (SR)‐stress accompanied by activation unfolded protein response (UPR) often precedes clearance machinery and represents a cellular defense mechanism toward...
The human Sec61 complex is a widely distributed and abundant molecular machine. It resides in the membrane of endoplasmic reticulum to channel two types cargo: protein substrates calcium ions. SEC61A1 gene encodes for pore-forming Sec61α subunit complex. Despite their ubiquitous expression, idiopathic missense mutations p.V67G p.T185A trigger localized disease pattern diagnosed as autosomal dominant tubulointerstitial kidney (ADTKD– ). Using cellular models ADTKD– , we identified an impaired...