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Transferrin Recycling

Ryohei Sakai, Ryosuke Fukuda, Shin Unida, Misaki Aki, Yuji Ono, Akinori Endo, Satoshi Kusumi, Daisuke Koga, Toshiaki Fukushima, Masayuki Komada, Tsukasa Okiyoneda
Endocytic trafficking is regulated by ubiquitination of cargoes and endocytic machineries. The role of ubiquitination in lysosomal delivery has been well documented, but that in the recycling pathway is largely unknown. Here we report that ubiquitin (Ub) ligase RFFL regulates ubiquitination of endocytic recycling regulators. RFFL dominant-negative (DN) mutant induced clustered endocytic recycling compartments (ERC) and delayed endocytic cargo recycling without affecting lysosomal traffic. BioID RFFL interactome analysis revealed that RFFL interacts with Rab11 effectors EHD1, MICALL1 and class I Rab11-FIPs...
January 18, 2019: Journal of Cell Science
Madeline Neiveyans, Rana Melhem, Christophe Arnoult, Thomas Bourquard, Marta Jarlier, Muriel Busson, Adrien Laroche, Martine Cerutti, Martine Pugnières, David Ternant, Nadège Gaborit, Thierry Chardès, Anne Poupon, Valérie Gouilleux-Gruart, Andre Pèlegrin, Marie-Alix Poul
Targeting transferrin receptor 1 (TfR1) with monoclonal antibodies is a promising therapeutic strategy in cancer as tumor cells often overexpress TfR1 and show increased iron needs. We have re-engineered six anti-human TfR1 single-chain variable fragment (scFv) antibodies into fully human scFv2 -Fcγ1 and IgG1 antibodies. We selected the more promising candidate (H7), based on its ability to inhibit TfR1-mediated iron-loaded transferrin internalization in Raji cells (B-cell lymphoma). The H7 antibody displayed nanomolar affinity for its target in both formats (scFv2 -Fcγ1 and IgG1), but cross-reacted with mouse TfR1 only in the scFv2 -Fc format...
January 3, 2019: MAbs
Kamil Brzóska, Teresa Bartłomiejczyk, Barbara Sochanowicz, Magdalena Cymerman, Jacek Grudny, Jacek Kołakowski, Marcin Kruszewski, Paweł Śliwiński, Kazimierz Roszkowski-Śliż, Lucyna Kapka-Skrzypczak
Chronic obstructive pulmonary disease (COPD) is often accompanied by lung cancer. In our previous work, it was observed that matrix metalloproteinase-3 and haptoglobin ( HP ) polymorphisms were potential markers of enhanced susceptibility to lung cancer development among male COPD subjects. Here, results are reported on blood serum levels of several proteins involved in iron metabolism, inflammation and the oxidative stress response compared between the same groups of subjects. The blood serum levels of tumor necrosis factor α (TNFα), transferrin, hepcidin, ferritin, soluble transferrin receptor and 8-oxo-2'-deoxyguanosine were compared, as well as total iron-binding capacity (TIBC) and ceruloplasmin ferroxidase activity in two groups of subjects: Male COPD patients (54 subjects) and male COPD patients diagnosed with lung cancer (53 subjects)...
November 2018: Oncology Letters
M Krijt, A Jirkovska, T Kabickova, V Melenovsky, J Petrak, D Vyoral
Dysregulated iron metabolism has a detrimental effect on cardiac function. The importance of iron homeostasis in cardiac health and disease warrants detailed studies of cardiomyocyte iron uptake, utilization and recycling at the molecular level. In this study, we have performed metabolic labeling of primary cultures of neonatal rat cardiomyocytes with radioactive iron coupled with separation of labeled iron-containing molecules by native electrophoresis followed by detection and quantification of incorporated radioiron by storage phosphorimaging...
September 10, 2018: Biochimica et biophysica acta. General subjects
Shuling Zhao, Dongdong Wang, Shuqiang Zhu, Xiaoyan Liu, Haixia Zhang
A green and promising sample pretreatment method was successfully established, which efficiently isolated proteins and small molecules in human serum. This method was achieved based on the multifunctional polymer, cryogel, as a solid phase extraction (SPE) monolith easily equipped in a syringe. The cryogel (pDC/GO-DE) was composed of diallyldimethyl ammonium chloride (DC) and 2-hydroxyethyl methacrylate (HE), which was further modified with graphene oxide (GO) and N-diethylethanamine hydrobromide (DE). Various proteins, including bovine serum albumin (BSA), lysozyme (Lys), γ-globulins, immunoglobulin G (IgG), transferrin, small molecules (ribavirin, adenosine, ofloxacin, estriol, rutin, amoxicillin, ibuprofen, 1-methyl-3-phenyl-propylamine, and benzylamine) and their mixtures were successively studied as model analytes to evaluate the new material and demonstrate the isolation mechanism, which was mainly dependent on mixed-mode ion-exchange and the hybrid hydrophobicity-hydrophilicity property of pDC/GO-DE cryogel...
January 1, 2019: Talanta
Megan T Harris, Syed Saad Hussain, Candice M Inouye, Anna M Castle, J David Castle
The ABC transporter ABCG1 contributes to the regulation of cholesterol efflux from cells and to the distribution of cholesterol within cells. We showed previously that ABCG1 deficiency inhibits insulin secretion by pancreatic beta cells and, based on its immunolocalization to insulin granules, proposed its essential role in forming granule membranes that are enriched in cholesterol. While we confirm elsewhere that ABCG1, alongside ABCA1 and oxysterol binding protein OSBP, supports insulin granule formation, the aim here is to clarify the localization of ABCG1 within insulin-secreting cells and to provide added insight regarding ABCG1's trafficking and sites of function...
2018: PloS One
Tomoko Kimura, Takahiro Kuragano, Kiyoko Yamamoto, Masayoshi Nanami, Yukiko Hasuike, Takeshi Nakanishi
Although the primary cause of anemia in chronic kidney disease (CKD) is lack of sufficient erythropoietin (EPO), other factors may be involved, including the deregulation of iron metabolism. To clarify the mechanism of deranged erythropoiesis in CKD, we evaluated bone marrow (BM) cells in adenine-induced CKD mice. They showed even higher EPO expression in the kidney. Hepatic hepcidin mRNA and plasma hepcidin and ferritin levels were increased. Flow cytometry revealed a decrease in the number of cells expressing transferrin receptor (TfR), or late erythroid progenitors in BM; these cells correspond to proerythroblasts, and basophilic and polychromatic erythroblasts...
September 19, 2018: International Journal of Hematology
Brie K Fuqua, Yan Lu, David M Frazer, Deepak Darshan, Sarah J Wilkins, Linda Dunn, Alex V Loguinov, Scott C Kogan, Pavle Matak, Huijun Chen, Joshua L Dunaief, Chris D Vulpe, Gregory J Anderson
Background & Aims: Multicopper ferroxidases (MCFs) facilitate intestinal iron absorption and systemic iron recycling, likely by a mechanism involving the oxidization of Fe2+ from the iron exporter ferroportin 1 for delivery to the circulating Fe3+ carrier transferrin. Hephaestin (HEPH), the only MCF known to be expressed in enterocytes, aids in the basolateral transfer of dietary iron to the blood. Mice lacking HEPH in the whole body ( Heph -/- ) or intestine alone ( Heph int/int ) exhibit defects in dietary iron absorption but still survive and grow...
2018: Cellular and Molecular Gastroenterology and Hepatology
Dhaval Patel, Stephan N Witt
Retromer is a phylogenetically conserved, multisubunit coat complex that controls endosomal protein trafficking and sorting. Mutations in the retromer gene VPS35 cause late-onset Parkinson disease, suggesting that trafficking defects cause neurodegeneration. Sorting nexins assist retromer to guide cell surface proteins to their assigned destinations, and our interest here is sorting nexin 3 (Snx3). Snx3 binds to membranes via a phox homolog (PX) domain that binds phosphatidylinositol 3-phosphate (PI3P), and in human cells its cargo proteins are the transferrin and Wnt receptors and the divalent metal ion transporter, whereas in yeast the best characterized cargo is the iron permease Ftr1...
2018: Journal of Experimental Neuroscience
Pierre Brissot, Delphine G Bernard, Eolia Brissot, Olivier Loréal, Marie-Bérengère Troadec
Anemia is defined by a deficiency of hemoglobin, an iron-rich protein that binds oxygen in the blood. It can be due to multiple causes, either acquired or genetic. Alterations of genes involved in iron metabolism may be responsible, usually at a young age, for rare forms of chronic and often severe congenital anemia. These diseases encompass a variety of sideroblastic anemias, characterized by the presence of ring sideroblasts in the bone marrow. Clinical expression of congenital sideroblastic anemia is either monosyndromic (restricted to hematological lineages) or polysyndromic (with systemic expression), depending on whether iron metabolism, and especially heme synthesis, is directly or indirectly affected...
July 2018: Mutation Research
Xiaoning Song, Rui Li, Hailiang Deng, Ye Li, Yanan Cui, Hua Zhang, Wenbing Dai, Bing He, Ying Zheng, Xueqing Wang, Qiang Zhang
Active-targeting nanocarriers can significantly improve the transcytosis of poorly water-soluble or bio-macromolecular drugs across biological barrier. However, reasons for the improvement are not understood enough, which hampered the reasonable design of active targeting nanocarriers. To illustrate how different factors influence the transport of active-targeting nanocarriers, we established ligand-decorated micelles targeting different receptors to study how the decorations influence the transcytosis of the micelles by comparing the endocytosis, transport pathway and exocytosis process...
October 2018: Biomaterials
Adam W Ware, Tanya T Cheung, Sahib Rasulov, Ezra Burstein, Fiona J McDonald
Optimal function of the epithelial sodium channel (ENaC) in the distal nephron is key to the kidney's long-term control of salt homeostasis and blood pressure. Multiple pathways alter ENaC cell surface populations, including correct processing and trafficking in the secretory pathway to the cell surface, and retrieval from the cell surface through ubiquitination by the ubiquitin ligase Nedd4-2, clathrin-mediated endocytosis, and sorting in the endosomal system. Members of the Copper Metabolism Murr1 Domain containing (COMMD) family of 10 proteins are known to interact with ENaC...
2018: Frontiers in Physiology
Lingxiao Tan, Kwang-Jin Cho, Pratik Neupane, Robert J Capon, John F Hancock
Oncogenic RAS proteins are commonly expressed in human cancer. To be functional, RAS proteins must undergo post-translational modification and localize to the plasma membrane (PM). Therefore, compounds that prevent RAS PM targeting have potential as putative RAS inhibitors. Here we examine the mechanism of action of oxanthroquinone G01 (G01), a recently described inhibitor of KRAS PM localization. We show that G01 mislocalizes HRAS and KRAS from the PM with similar potency and disrupts the spatial organization of RAS proteins remaining on the PM...
August 31, 2018: Journal of Biological Chemistry
Tetyana Gryaznova, Olga Gubar, Mariia Burdyniuk, Sergii Kropyvko, Alla Rynditch
WIP (WASP interacting protein) together with N-WASP (neural Wiskott-Aldrich syndrome protein) regulates actin polymerization that is crucial for invadopodia and filopodia formation. Recently, we reported the WIP interaction with ITSN1 which is highly implicated in endo-/exocytosis, apoptosis, mitogenic signaling and cytoskeleton rearrangements. Here we demonstrate that the WIP/ITSN1 complex is involved in the transferrin receptor recycling and partially co-localizes with a marker of the fast recycling endosomes, RAB4...
October 20, 2018: Gene
Yasuhiro Moriwaki, Yuho Ohno, Tomohiro Ishii, Yuki Takamura, Yuko Kita, Kazuhiko Watabe, Kazunori Sango, Shoutaro Tsuji, Hidemi Misawa
Small integral membrane protein of the lysosome/late endosome (SIMPLE) is a 161-amino acid cellular protein that contains a characteristic C-terminal domain known as the SIMPLE-like domain (SLD), which is well conserved among species. Several studies have demonstrated that SIMPLE localizes to the trans-Golgi network (TGN), early endosomes, lysosomes, multivesicular bodies, aggresomes and the plasma membrane. However, the amino acid regions responsible for its subcellular localization have not yet been identified...
2018: PloS One
Ewan MacDonald, Louise Brown, Arnaud Selvais, Han Liu, Thomas Waring, Daniel Newman, Jessica Bithell, Douglas Grimes, Sylvie Urbé, Michael J Clague, Tobias Zech
Transmembrane proteins in the sorting endosome are either recycled to their point of origin or destined for lysosomal degradation. Lysosomal sorting is mediated by interaction of ubiquitylated transmembrane proteins with the endosomal sorting complex required for transport (ESCRT) machinery. In this study, we uncover an alternative role for the ESCRT-0 component hepatocyte growth factor-regulated tyrosine kinase substrate (HRS) in promoting the constitutive recycling of transmembrane proteins. We find that endosomal localization of the actin nucleating factor Wiscott-Aldrich syndrome protein and SCAR homologue (WASH) requires HRS, which occupies adjacent endosomal subdomains...
July 2, 2018: Journal of Cell Biology
Lipsa Das, Jaime M C Gard, Rytis Prekeris, Raymond B Nagle, Colm Morrissey, Beatrice S Knudsen, Cindy K Miranti, Anne E Cress
The laminin-binding integrins, α3β1 and α6β1, are needed for tumor metastasis and their surface expression is regulated by endocytic recycling. β1 integrins share the Rab11 recycling machinery, but the trafficking of α3β1 and α6β1 are distinct by an unknown mechanism. Using a mouse PDX tumor model containing human metastatic prostate cancer, Rab11 family interacting protein 5 (Rab11-FIP5) was identified as a lead candidate for α6β1 trafficking. Rab11-FIP5 and its membrane-binding domain were required for α6β1 recycling, without affecting the other laminin-binding integrin (i...
August 2018: Molecular Cancer Research: MCR
Heather E Miller, Charles L Larson, Robert A Heinzen
Coxiella burnetii is an intracellular bacterium that replicates within an expansive phagolysosome-like vacuole. Fusion between the Coxiella-containing vacuole (CCV) and late endosomes/multivesicular bodies requires Rab7, the HOPS tethering complex, and SNARE proteins, with actin also speculated to play a role. Here, we investigated the importance of actin in CCV fusion. Filamentous actin patches formed around the CCV membrane that were preferred sites of vesicular fusion. Accordingly, the mediators of endolysosomal fusion Rab7, VAMP7, and syntaxin 8 were concentrated in CCV actin patches...
April 2018: PLoS Pathogens
Joydeep Sarkar, Alka A Potdar, Gerald M Saidel
Iron plays vital roles in the human body including enzymatic processes, oxygen-transport via hemoglobin and immune response. Iron metabolism is characterized by ~95% recycling and minor replenishment through diet. Anemia of chronic kidney disease (CKD) is characterized by a lack of synthesis of erythropoietin leading to reduced red blood cell (RBC) formation and aberrant iron recycling. Treatment of CKD anemia aims to normalize RBC count and serum hemoglobin. Clinically, the various fluxes of iron transport and accumulation are not measured so that changes during disease (e...
April 2018: PLoS Computational Biology
Andre C M DeGroot, David J Busch, Carl C Hayden, Samuel A Mihelic, Aaron T Alpar, Marcelo Behar, Jeanne C Stachowiak
Receptor internalization by endocytosis regulates diverse cellular processes, from the rate of nutrient uptake to the timescale of essential signaling events. The established view is that internalization is tightly controlled by specific protein-binding interactions. However, recent work suggests that physical aspects of receptors influence the process in ways that cannot be explained by biochemistry alone. Specifically, work from several groups suggests that increasing the steric bulk of receptors may inhibit their uptake by multiple types of trafficking vesicles...
March 27, 2018: Biophysical Journal
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