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Early endosome

Jeffrey Zielich, Elena Tzima, Eva Ayla Schröder, Faten Jemel, Barbara Conradt, Eric J Lambie
P5B ATPases are present in the genomes of diverse unicellular and multicellular eukaryotes, indicating that they have an ancient origin, and that they are important for cellular fitness. Inactivation of ATP13A2, one of the four human P5B ATPases, leads to early-onset Parkinson's disease (Kufor-Rakeb Syndrome). The presence of an invariant PPALP motif within the putative substrate interaction pocket of transmembrane segment M4 suggests that all P5B ATPases might have similar transport specificity; however, the identity of the transport substrate(s) remains unknown...
2018: PloS One
Nicola L D Overton, Axel A Brakhage, Andreas Thywißen, David W Denning, Paul Bowyer
Allergic bronchopulmonary aspergillosis (ABPA) in asthma is a severe, life-affecting disease that potentially affects over 4.8 million people globally. In the UK, ABPA is predominantly caused by the fungus Aspergillus fumigatus. Phagocytosis is important in clearance of this fungus, and Early Endosome Antigen 1 (EEA1) has been demonstrated to be involved in phagocytosis of fungi. We sought to investigate the role of EEA1 mutations and phagocytosis in ABPA. We used exome sequencing to identify variants in EEA1 associated with ABPA...
2018: PloS One
A Covarrubias-Pinto, A I Acuña, G Boncompain, E Pápic, P V Burgos, F Perez, M A Castro
Ascorbic acid (Asc) is an antioxidant molecule essential for physiological functions. The concentration of extracellular Asc increases during synaptic transmission and renal reabsorption. These phenomena induce an increase of the Sodium-dependent-Vitamin-C-transporter 2 (SVCT2) at plasma membrane (PM) localization, as we previously demonstrated in neuronal and non-neuronal cells. Hence, the aim of this study was to evaluate intracellular SVCT2 trafficking kinetics in response to Asc. We observed two peaks of SVCT2 localization and function at the PM (at 5-10min, "acute response", and 30-60min, "post-acute response") when cells were incubated with Asc...
March 12, 2018: Free Radical Biology & Medicine
Jonas Reinholz, Christopher Diesler, Susanne Schöttler, Maria Kokkinopoulou, Sandra Ritz, Katharina Landfester, Volker Mailänder
The transport of nanocarriers through barriers like the gut in a living organism involves the transcytosis of these nanocarriers through the cell layer dividing two compartments. Understanding how this process works is not only essential to further developing strategies for a more effective nanocarrier transport system but also for providing fundamental insights into the barrier function as a means of protection against micro- and nanoplastics in the food chain. We therefore set out to investigate the different uptake mechanisms, intracellular trafficking and the routes for exocytosis for small polystyrene nanoparticles (PS-NPs ca...
March 9, 2018: Acta Biomaterialia
Julie A Gosney, Daniel W Wilkey, Michael L Merchant, Brian P Ceresa
The epidermal growth factor receptor (EGFR) is a receptor tyrosine kinase that is an integral component of proliferative signaling. EGFRs on the cell surface become activated upon epidermal growth factor (EGF) binding and have an increased rate of endocytosis. Once in the cytoplasm, the EGF:EGFR complex is trafficked to the lysosome for degradation and signaling is terminated. During trafficking, the EGFR kinase domain remains active and the internalized EGFR can continue signaling to downstream effectors. While effector activity varies based on the EGFR's endocytic location, it is not clear how this occurs...
March 9, 2018: Journal of Biological Chemistry
Jenny Chia, Jade Louber, Isabelle Glauser, Shirley Taylor, Greg T Bass, Steve K Dower, Paul A Gleeson, Anne M Verhagen
The neonatal Fc receptor (FcRn) has a pivotal role in albumin and IgG homeostasis. Internalized IgG captured by FcRn under acidic endosomal conditions is recycled to the cell surface where exocytosis and a shift to neutral pH promote extracellular IgG release. Although a similar mechanism is proposed for FcRn-mediated albumin intracellular trafficking and recycling, this pathway is less well defined, but is relevant to the development of therapeutics exploiting FcRn to extend the half-life of short-lived plasma proteins...
March 9, 2018: Journal of Biological Chemistry
Kaiyi Zhang, Ambre Riba, Monika Nietschke, Natalia Torow, Urska Repnik, Andreas Pütz, Marcus Fulde, Aline Dupont, Michael Hensel, Mathias Hornef
Effector molecules translocated by the Salmonella pathogenicity island (SPI)1-encoded type 3 secretion system (T3SS) critically contribute to the pathogenesis of human Salmonella infection. They facilitate internalization by non-phagocytic enterocytes rendering the intestinal epithelium an entry site for infection. Their function in vivo has remained ill-defined due to the lack of a suitable animal model that allows visualization of intraepithelial Salmonella. Here, we took advantage of our novel neonatal mouse model and analyzed various bacterial mutants and reporter strains as well as gene deficient mice...
March 9, 2018: PLoS Pathogens
Marc Lenoir, Cansel Ustunel, Sandya Rajesh, Jaswant Kaur, Dimitri Moreau, Jean Gruenberg, Michael Overduin
Sorting nexins anchor trafficking machines to membranes by binding phospholipids. The paradigm of the superfamily is sorting nexin 3 (SNX3), which localizes to early endosomes by recognizing phosphatidylinositol 3-phosphate (PI3P) to initiate retromer-mediated segregation of cargoes to the trans-Golgi network (TGN). Here we report the solution structure of full length human SNX3, and show that PI3P recognition is accompanied by bilayer insertion of a proximal loop in its extended Phox homology (PX) domain. Phosphoinositide (PIP) binding is completely blocked by cancer-linked phosphorylation of a conserved serine beside the stereospecific PI3P pocket...
March 8, 2018: Nature Communications
Dominga Fasano, Silvia Parisi, Giovanna Maria Pierantoni, Anna De Rosa, Marina Picillo, Giuseppina Amodio, Maria Teresa Pellecchia, Paolo Barone, Ornella Moltedo, Vincenzo Bonifati, Giuseppe De Michele, Lucio Nitsch, Paolo Remondelli, Chiara Criscuolo, Simona Paladino
Recently, a new form of autosomal recessive early-onset parkinsonism (PARK20), due to mutations in the gene encoding the phosphoinositide phosphatase, Synaptojanin 1 (Synj1), has been reported. Several genes responsible for hereditary forms of Parkinson's disease are implicated in distinct steps of the endolysosomal pathway. However, the nature and the degree of endocytic membrane trafficking impairment in early-onset parkinsonism remains elusive. Here, we show that depletion of Synj1 causes drastic alterations of early endosomes, which become enlarged and more numerous, while it does not affect the morphology of late endosomes both in non-neuronal and neuronal cells...
March 7, 2018: Cell Death & Disease
Jing Shi, Ran Xiong, Tao Zhou, Peiyi Su, Xihe Zhang, Xusheng Qiu, Hongmei Li, Sunan Li, Changqing Yu, Bin Wang, Chan Ding, Thomas E Smithgall, Yong-Hui Zheng
The primate lentiviral accessory protein Nef downregulates CD4 and MHC-I from the cell surface via independent endosomal trafficking pathways to promote viral pathogenesis. In addition, Nef antagonizes a novel restriction factor, SERINC5 (Ser5), to increase viral infectivity. To explore the molecular mechanism of Ser5 antagonism by Nef, we determined how Nef affects Ser5 expression and intracellular trafficking in comparison with CD4 and MHC-I. We confirm that Nef excludes Ser5 from HIV-1 virions by downregulating its cell surface expression via similar functional motifs required for CD4-downregulation...
March 7, 2018: Journal of Virology
Shiyu Wang, Nickolas Allen, Timothy A Vickers, Alexey S Revenko, Hong Sun, Xue-Hai Liang, Stanley T Crooke
Chemically modified antisense oligonucleotides (ASOs) with phosphorothioate (PS) linkages have been extensively studied as research and therapeutic agents. PS-ASOs can enter the cell and trigger cleavage of complementary RNA by RNase H1 even in the absence of transfection reagent. A number of cell surface proteins have been identified that bind PS-ASOs and mediate their cellular uptake; however, the mechanisms that lead to productive internalization of PS-ASOs are not well understood. Here, we characterized the interaction between PS-ASOs and epidermal growth factor receptor (EGFR)...
March 5, 2018: Nucleic Acids Research
Danny Mollerup Sørensen, Tine Holemans, Sarah van Veen, Shaun Martin, Tugce Arslan, Ida Winther Haagendahl, Henrik Waldal Holen, Norin Nabil Hamouda, Jan Eggermont, Michael Palmgren, Peter Vangheluwe
Several human P5-type transport ATPases are implicated in neurological disorders, but little is known about their physiological function and properties. Here, we investigated the relationship between the five mammalian P5 isoforms ATP13A1-5 in a comparative study. We demonstrated that ATP13A1-4 isoforms undergo autophosphorylation, which is a hallmark P-type ATPase property that is required for substrate transport. A phylogenetic analysis of P5 sequences revealed that ATP13A1 represents clade P5A, which is highly conserved between fungi and animals with one member in each investigated species...
2018: PloS One
Gati K Panigrahi, Prakash P Praharaj, Taylor C Peak, Jessica Long, Ravi Singh, Johng S Rhim, Zakaria Y Abd Elmageed, Gagan Deep
African American men in the United States have higher mortality due to prostate cancer (PCa) compared to other races. One reason for this disparity is the lack of in-depth understanding of the PCa biology in African Americans. For example, hypoxia in prostate tumor microenvironment is associated with adverse prognosis; still, no hypoxia-related studies have been reported in African Americans. Here, we compared African-American and Caucasian PCa cells for exosome secretion under normoxic (21% O2 ) and hypoxic (1% O2 ) conditions...
March 1, 2018: Scientific Reports
Nao Sakurai, Shunsuke Nishio, Yuka Akiyama, Shinji Miyata, Kenzi Oshima, Daita Nadano, Tsukasa Matsuda
Casein is the major milk protein to nourish infants but, in certain population, it causes cow's milk allergy, indicating the uptake of antigenic casein and their peptides through the intestinal epithelium. Using human intestinal Caco-2 cell monolayers, the apical-to-basal transepithelial transport of casein was investigated. Confocal microscopy using component-specific antibodies showed that αs1-casein antigens became detectable as punctate signals at the apical-side cytoplasm and reached to the cytoplasm at a tight-junction level within a few hours...
February 27, 2018: Journal of Biochemistry
Daniela Sparvoli, Elisabeth Richardson, Hiroko Osakada, Xun Lan, Masaaki Iwamoto, Grant R Bowman, Cassandra Kontur, William A Bourland, Denis H Lynn, Jonathan K Pritchard, Tokuko Haraguchi, Joel B Dacks, Aaron P Turkewitz
In the endocytic pathway of animals, two related complexes, called CORVET (class C core vacuole/endosome transport) and HOPS (homotypic fusion and protein sorting), act as both tethers and fusion factors for early and late endosomes, respectively. Mutations in CORVET or HOPS lead to trafficking defects and contribute to human disease, including immune dysfunction. HOPS and CORVET are conserved throughout eukaryotes, but remarkably, in the ciliate Tetrahymena thermophila, the HOPS-specific subunits are absent, while CORVET-specific subunits have proliferated...
February 21, 2018: Current Biology: CB
C T H Jonker, R Galmes, T Veenendaal, C Ten Brink, R E N van der Welle, N Liv, J de Rooij, A A Peden, P van der Sluijs, C Margadant, J Klumperman
Recycling endosomes maintain plasma membrane homeostasis and are important for cell polarity, migration, and cytokinesis. Yet, the molecular machineries that drive endocytic recycling remain largely unclear. The CORVET complex is a multi-subunit tether required for fusion between early endosomes. Here we show that the CORVET-specific subunits Vps3 and Vps8 also regulate vesicular transport from early to recycling endosomes. Vps3 and Vps8 localise to Rab4-positive recycling vesicles and co-localise with the CHEVI complex on Rab11-positive recycling endosomes...
February 23, 2018: Nature Communications
FoSheng Hsu, Stephanie Spannl, Charles Ferguson, Anthony A Hyman, Robert G Parton, Marino Zerial
Mitochondrial stress response is essential for cell survival, and damaged mitochondria are a hallmark of neurodegenerative diseases. Thus, it is fundamental to understand how mitochondria relay information within the cell. Here, by investigating mitochondrial-endosomal contact sites we made the surprising observation that the small GTPase Rab5 translocates from early endosomes to mitochondria upon oxidative stress. This process is reversible and accompanied by an increase in Rab5-positive endosomes in contact with mitochondria...
February 22, 2018: ELife
Xue-Ming Zhu, Shuang Liang, Huan-Bin Shi, Jian-Ping Lu, Bo Dong, Qian-Sheng Liao, Fu-Cheng Lin, Xiao-Hong Liu
Pyricularia oryzae is the causal pathogen of rice blast disease. Autophagy has been shown to play important roles in P. oryzae development and plant infection. The P. oryzae endosomal system is highly dynamic and has been shown to be associated with conidiogenesis and pathogenicity as well. To date, the crosstalk between autophagy and endocytosis has not been explored in P. oryzae. Here, we identified three P. oryzae VPS9 domain-containing proteins, PoVps9, PoMuk1, and PoVrl1. We found that PoVps9 and PoMuk1 are localized to vesicles and are each co-localized with PoVps21, a recognized marker of early endosomes...
February 22, 2018: Environmental Microbiology
Thomas O'Loughlin, Thomas A Masters, Folma Buss
The intracellular functions of myosin motors requires a number of adaptor molecules, which control cargo attachment, but also fine-tune motor activity in time and space. These motor-adaptor-cargo interactions are often weak, transient or highly regulated. To overcome these problems, we use a proximity labelling-based proteomics strategy to map the interactome of the unique minus end-directed actin motor MYO6. Detailed biochemical and functional analysis identified several distinct MYO6-adaptor modules including two complexes containing RhoGEFs: the LIFT (LARG-Induced F-actin for Tethering) complex that controls endosome positioning and motility through RHO-driven actin polymerisation; and the DISP (DOCK7-Induced Septin disPlacement) complex, a novel regulator of the septin cytoskeleton...
February 21, 2018: EMBO Reports
Sabrina Maisel, Derrick Broka, Joyce Schroeder
The Epidermal Growth Factor Receptor (EGFR) is frequently mutated and overexpressed in metastatic cancer. Although EGFR is a transmembrane tyrosine kinase localized to the basolateral membrane in normal epithelium, it is frequently found intracellularly localized in transformed cells. We have previously demonstrated the epithelial adaptor protein mucin 1 (MUC1) alters trafficking of EGFR, inhibiting its degradation and promoting its translocation to the nucleus, where it can directly modulate gene transcription...
January 19, 2018: Oncotarget
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