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Sorting nexin

Tzvetina Brumbarova, Rumen Ivanov
Endosomal recycling of plasma membrane proteins contributes significantly to the regulation of cellular transport and signaling processes. Members of the Arabidopsis (Arabidopsis thaliana) SORTING NEXIN (SNX) protein family were shown to mediate the endosomal retrieval of transporter proteins in response to external challenges. Our aim is to understand the possible ways through which external stimuli influence the activity of SNX1 in the root. Several proteins are known to contribute to the function of SNX1 through direct protein-protein interaction...
2016: Frontiers in Plant Science
Ketaki Ganti, Paola Massimi, Joaquin Manzo-Merino, Vjekoslav Tomaić, David Pim, Martin P Playford, Marcela Lizano, Sally Roberts, Christian Kranjec, John Doorbar, Lawrence Banks
A subset of high-risk Human Papillomaviruses (HPVs) are the causative agents of a large number of human cancers, of which cervical is the most common. Two viral oncoproteins, E6 and E7, contribute directly towards the development and maintenance of malignancy. A characteristic feature of the E6 oncoproteins from cancer-causing HPV types is the presence of a PDZ binding motif (PBM) at its C-terminus, which confers interaction with cellular proteins harbouring PDZ domains. Here we show that this motif allows E6 interaction with Sorting Nexin 27 (SNX27), an essential component of endosomal recycling pathways...
September 2016: PLoS Pathogens
Shanna Lynn Bowman, Daniel John Shiwarski, Manojkumar A Puthenveedu
G protein-coupled receptors (GPCRs) are recycled via a sequence-dependent pathway that is spatially and biochemically distinct from bulk recycling. Why there are two distinct recycling pathways from the endosome is a fundamental question in cell biology. In this study, we show that the separation of these two pathways is essential for normal spatial encoding of GPCR signaling. The prototypical β-2 adrenergic receptor (B2AR) activates Gα stimulatory protein (Gαs) on the endosome exclusively in sequence-dependent recycling tubules marked by actin/sorting nexin/retromer tubular (ASRT) microdomains...
September 26, 2016: Journal of Cell Biology
Thomas Clairfeuille, Caroline Mas, Audrey S M Chan, Zhe Yang, Maria Tello-Lafoz, Mintu Chandra, Jocelyn Widagdo, Markus C Kerr, Blessy Paul, Isabel Mérida, Rohan D Teasdale, Nathan J Pavlos, Victor Anggono, Brett M Collins
Recycling of internalized receptors from endosomal compartments is essential for the receptors' cell-surface homeostasis. Sorting nexin 27 (SNX27) cooperates with the retromer complex in the recycling of proteins containing type I PSD95-Dlg-ZO1 (PDZ)-binding motifs. Here we define specific acidic amino acid sequences upstream of the PDZ-binding motif required for high-affinity engagement of the human SNX27 PDZ domain. However, a subset of SNX27 ligands, such as the β2 adrenergic receptor and N-methyl-D-aspartate (NMDA) receptor, lack these sequence determinants...
October 2016: Nature Structural & Molecular Biology
Joe Fenn, Mike Boursnell, Rebekkah J Hitti, Christopher A Jenkins, Rebecca L Terry, Simon L Priestnall, Patrick J Kenny, Cathryn S Mellersh, Oliver P Forman
BACKGROUND: Cerebellar cortical degeneration (CCD) is an increasingly recognised neurodegenerative disease process affecting many dog breeds. Typical presentation consists of a progressive cerebellar ataxia, with a variable age at onset and rate of progression between different breeds. Cerebellar histopathological findings typically consist of primary Purkinje neuronal degeneration and loss, with variable secondary depletion of the granular and molecular cell layers. Causative genes have been identified associated with CCD in several breeds, allowing screening for selective breeding to reduce the prevalence of these conditions...
2016: BMC Genetics
Qiushi Li, Xidong Li, Li Wang, Yanhui Zhang, Long Chen
Accumulation of amyloid β-peptide (Aβ) in the brain of Alzheimer disease (AD) patients is believed to be the main pathological feature of the disease. Meanwhile, miR-98-5p dysregulation was found in AD. However, whether miR-98-5p is involved in the accumulation of Aβ in AD, the underlying molecule mechanism remains unclear. In the present study, we confirmed that miR-98-5p negatively regulated sorting nexin 6 (SNX6) expression by targeting the 3'-UTR of SNX6 mRNA. Downregulation of miR-98-5p alleviated Aβ-induced viability inhibition and decreased apoptosis in SK-N-SH and SH-SY5Y cells by upregulating SNX6 expression...
August 19, 2016: Journal of Molecular Neuroscience: MN
Diana Matheoud, Ayumu Sugiura, Angélique Bellemare-Pelletier, Annie Laplante, Christiane Rondeau, Magali Chemali, Ali Fazel, John J Bergeron, Louis-Eric Trudeau, Yan Burelle, Etienne Gagnon, Heidi M McBride, Michel Desjardins
Antigen presentation is essential for establishing immune tolerance and for immune responses against infectious disease and cancer. Although antigen presentation can be mediated by autophagy, here we demonstrate a pathway for mitochondrial antigen presentation (MitAP) that relies on the generation and trafficking of mitochondrial-derived vesicles (MDVs) rather than on autophagy/mitophagy. We find that PINK1 and Parkin, two mitochondrial proteins linked to Parkinson's disease (PD), actively inhibit MDV formation and MitAP...
July 14, 2016: Cell
Catherine Marquer, Huasong Tian, Julie Yi, Jayson Bastien, Claudia Dall'Armi, YoungJoo Yang-Klingler, Bowen Zhou, Robin Barry Chan, Gilbert Di Paolo
Small GTPases play a critical role in membrane traffic. Among them, Arf6 mediates transport to and from the plasma membrane, as well as phosphoinositide signalling and cholesterol homeostasis. Here we delineate the molecular basis for the link between Arf6 and cholesterol homeostasis using an inducible knockout (KO) model of mouse embryonic fibroblasts (MEFs). We find that accumulation of free cholesterol in the late endosomes/lysosomes of Arf6 KO MEFs results from mistrafficking of Niemann-Pick type C protein NPC2, a cargo of the cation-independent mannose-6-phosphate receptor (CI-M6PR)...
2016: Nature Communications
Nawal Bendris, Carrie J S Stearns, Carlos R Reis, Jaime Rodriguez-Canales, Hui Liu, Agnieszka W Witkiewicz, Sandra L Schmid
The ability of cancer cells to degrade the extracellular matrix and invade interstitial tissues contributes to their metastatic potential. We recently showed that overexpression of sorting nexin 9 (SNX9) leads to increased cell invasion and metastasis in animal models, which correlates with increased SNX9 protein expression in metastases from human mammary cancers. Here, we report that SNX9 expression is reduced relative to neighboring normal tissues in primary breast tumors, and progressively reduced in more aggressive stages of non-small-cell lung cancers...
July 15, 2016: Journal of Cell Science
Sophie Erhardt, Lilly Schwieler, Sophie Imbeault, Göran Engberg
The kynurenine pathway of tryptophan degradation generates several neuroactive compounds. Of those, kynurenic acid is an N-methyl-d-aspartate (NMDA) and alpha7 nicotinic receptor antagonist. The kynurenic acid hypothesis of schizophrenia is built upon the fact that kynurenic acid blocks glutamate receptors and is elevated in schizophrenia. Kynurenic acid tightly controls glutamatergic and dopaminergic neurotransmission and elevated brain levels appear related to psychotic symptoms and cognitive impairments...
May 28, 2016: Neuropharmacology
Mitsunori Fukuda
VARP (VPS9-ankyrin-repeat protein, also known as ANKRD27) was originally identified as an N-terminal VPS9 (vacuolar protein sorting 9)-domain-containing protein that possesses guanine nucleotide exchange factor (GEF) activity toward small GTPase Rab21 and contains two ankyrin repeat (ANKR) domains in its central region. A number of VARP-interacting molecules have been identified during the past five years, and considerable attention is now being directed to the multiple roles of VARP in endosomal trafficking...
July 2016: Traffic
Laurie Ceccato, Gaëtan Chicanne, Virginie Nahoum, Véronique Pons, Bernard Payrastre, Frédérique Gaits-Iacovoni, Julien Viaud
Phosphoinositides are a type of cellular phospholipid that regulate signaling in a wide range of cellular and physiological processes through the interaction between their phosphorylated inositol head group and specific domains in various cytosolic proteins. These lipids also influence the activity of transmembrane proteins. Aberrant phosphoinositide signaling is associated with numerous diseases, including cancer, obesity, and diabetes. Thus, identifying phosphoinositide-binding partners and the aspects that define their specificity can direct drug development...
March 29, 2016: Science Signaling
Jennifer C McGarvey, Kunhong Xiao, Shanna L Bowman, Tatyana Mamonova, Qiangmin Zhang, Alessandro Bisello, W Bruce Sneddon, Juan A Ardura, Frederic Jean-Alphonse, Jean-Pierre Vilardaga, Manojkumar A Puthenveedu, Peter A Friedman
The G protein-coupled parathyroid hormone receptor (PTHR) regulates mineral-ion homeostasis and bone remodeling. Upon parathyroid hormone (PTH) stimulation, the PTHR internalizes into early endosomes and subsequently traffics to the retromer complex, a sorting platform on early endosomes that promotes recycling of surface receptors. The C terminus of the PTHR contains a type I PDZ ligand that binds PDZ domain-containing proteins. Mass spectrometry identified sorting nexin 27 (SNX27) in isolated endosomes as a PTHR binding partner...
May 20, 2016: Journal of Biological Chemistry
Chaosi Li, Syed Zahid Ali Shah, Deming Zhao, Lifeng Yang
The retromer complex is a protein complex that plays a central role in endosomal trafficking. Retromer dysfunction has been linked to a growing number of neurological disorders. The process of intracellular trafficking and recycling is crucial for maintaining normal intracellular homeostasis, which is partly achieved through the activity of the retromer complex. The retromer complex plays a primary role in sorting endosomal cargo back to the cell surface for reuse, to the trans-Golgi network (TGN), or alternatively to specialized endomembrane compartments, in which the cargo is not subjected to lysosomal-mediated degradation...
2016: Frontiers in Aging Neuroscience
Srijana Upadhyay, Xinping Xu, David Lowry, Jennifer C Jackson, Robert W Roberson, Xiaorong Lin
Protection by melanin depends on its subcellular location. Although most filamentous fungi synthesize melanin via a polyketide synthase pathway, where and how melanin biosynthesis occurs and how it is deposited as extracellular granules remain elusive. Using a forward genetic screen in the pathogen Aspergillus fumigatus, we find that mutations in an endosomal sorting nexin abolish melanin cell-wall deposition. We find that all enzymes involved in the early steps of melanin biosynthesis are recruited to endosomes through a non-conventional secretory pathway...
March 22, 2016: Cell Reports
Nawal Bendris, Karla C Williams, Carlos R Reis, Erik S Welf, Ping-Hung Chen, Bénédicte Lemmers, Michael Hahne, H S Leong, Sandra L Schmid
Despite current advances in cancer research, metastasis remains the leading factor in cancer-related deaths. Here, we identify sorting nexin 9 (SNX9) as a new regulator of breast cancer metastasis. We detected an increase in SNX9 expression in human breast cancer metastases compared with primary tumors and demonstrated that SNX9 expression in MDA-MB-231 breast cancer cells is necessary to maintain their ability to metastasize in a chick embryo model. Reciprocally, SNX9 knockdown impairs the process. In vitro studies using several cancer cell lines derived from a variety of human tumors revealed a role for SNX9 in cell invasion and identified mechanisms responsible for this novel function...
March 9, 2016: Molecular Biology of the Cell
Seongju Lee, Jaerak Chang, Craig Blackstone
The endosomal network maintains cellular homeostasis by sorting, recycling and degrading endocytosed cargoes. Retromer organizes the endosomal sorting pathway in conjunction with various sorting nexin (SNX) proteins. The SNX27-retromer complex has recently been identified as a major endosomal hub that regulates endosome-to-plasma membrane recycling by preventing lysosomal entry of cargoes. Here, we show that SNX27 directly interacts with FAM21, which also binds retromer, within the Wiskott-Aldrich syndrome protein and SCAR homologue (WASH) complex...
2016: Nature Communications
Marcel Vergés
Retromer is an evolutionary conserved protein complex required for endosome-to-Golgi retrieval of receptors for lysosomal hydrolases. It is constituted by a heterotrimer encoded by the vacuolar protein sorting (VPS) gene products Vps26, Vps35, and Vps29, which selects cargo, and a dimer of phosphoinositide-binding sorting nexins, which deforms the membrane. Recent progress in the mechanism of retromer assembly and functioning has strengthened the link between sorting at the endosome and cytoskeleton dynamics...
2016: International Review of Cell and Molecular Biology
Colin D H Ratcliffe, Pranshu Sahgal, Christine A Parachoniak, Johanna Ivaska, Morag Park
The integrin family of cell adhesion receptors link extracellular matrices to intracellular signaling pathways and the actin cytoskeleton; and regulate cell migration, proliferation and survival in normal and diseased tissues. The subcellular location of integrin receptors is critical for their function and deregulated trafficking is implicated in various human diseases. Here we identify a role for Golgi-localized gamma-ear containing Arf-binding protein 3 (GGA3), in regulating trafficking of β1 integrin. GGA3 knockdown reduces cell surface and total levels of α2, α5 and β1 integrin subunits, inhibits cell spreading, reduces focal adhesion number, as well as cell migration...
June 2016: Traffic
Audrey S M Chan, Thomas Clairfeuille, Euphemie Landao-Bassonga, Genevieve Kinna, Pei Ying Ng, Li Shen Loo, Tak Sum Cheng, Minghao Zheng, Wanjin Hong, Rohan D Teasdale, Brett M Collins, Nathan J Pavlos
The parathyroid hormone 1 receptor (PTHR) is central to the process of bone formation and remodeling. PTHR signaling requires receptor internalization into endosomes, which is then terminated by recycling or degradation. Here we show that sorting nexin 27 (SNX27) functions as an adaptor that couples PTHR to the retromer trafficking complex. SNX27 binds directly to the C-terminal PDZ-binding motif of PTHR, wiring it to retromer for endosomal sorting. The structure of SNX27 bound to the PTHR motif reveals a high-affinity interface involving conserved electrostatic interactions...
April 15, 2016: Molecular Biology of the Cell
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