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Sorting nexin

Akshay Bareja, Conrad P Hodgkinson, Erik Soderblom, Greg Waitt, Victor J Dzau
The insulin-like growth factor 1 receptor (IGF1R) is a receptor tyrosine kinase with critical roles in various biological processes. Recent results from clinical trials targeting IGF1R indicate that IGF1R signaling pathways are more complex than previously thought. Moreover, it has become increasingly clear that the function of many proteins can be understood only in the context of a network of interactions. To that end, we sought to profile IGF1R-protein interactions with the proximity-labeling technique BioID...
March 12, 2018: Journal of Biological Chemistry
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
Josyf C Mychaleckyj, Uma Nayak, E Ross Colgate, Dadong Zhang, Tommy Carstensen, Shahnawaz Ahmed, Tahmeed Ahmed, Alexander J Mentzer, Masud Alam, Beth D Kirkpatrick, Rashidul Haque, Abu Syed Golam Faruque, William A Petri
BACKGROUND: Breast milk is the sole nutrition source during exclusive breastfeeding, and polyunsaturated fatty acids (FAs) are critical micronutrients in infant physical and cognitive development. There has been no prior genomewide association study of breast milk, hence our objective was to test for genetic association with breast milk FA composition. METHODS: We measured the fractional composition of 26 individual FAs in breast milk samples from three cohorts totalling 1142 Bangladeshi mothers whose infants were genotyped on the Illumina MEGA chip and replicated on a custom Affymetrix 30K SNP array (n=616)...
March 7, 2018: Journal of Medical Genetics
Mohamed H Shahin, Daniela J Conrado, Daniel Gonzalez, Yan Gong, Maximilian T Lobmeyer, Amber L Beitelshees, Eric Boerwinkle, John G Gums, Arlene Chapman, Stephen T Turner, Rhonda M Cooper-DeHoff, Julie A Johnson
BACKGROUND: For many indications, the negative chronotropic effect of β-blockers is important to their efficacy, yet the heart rate (HR) response to β-blockers varies. Herein, we sought to use a genome-wide association approach to identify novel single nucleotide polymorphisms (SNPs) associated with HR response to β-blockers. METHODS AND RESULTS: We first performed 4 genome-wide association analyses for HR response to atenolol (a β1-adrenergic receptor blocker) as: (1) monotherapy or (2) add-on therapy, in 426 whites and 273 blacks separately from the PEAR (Pharmacogenomic Evaluation of Antihypertensive Responses) study...
February 24, 2018: Journal of the American Heart Association
Yuliya Salanenka, Inge Verstraeten, Christian Löfke, Kaori Tabata, Satoshi Naramoto, Matouš Glanc, Jiří Friml
The plant hormone gibberellic acid (GA) is a crucial regulator of growth and development. The main paradigm of GA signaling puts forward transcriptional regulation via the degradation of DELLA transcriptional repressors. GA has also been shown to regulate tropic responses by modulation of the plasma membrane incidence of PIN auxin transporters by an unclear mechanism. Here we uncovered the cellular and molecular mechanisms by which GA redirects protein trafficking and thus regulates cell surface functionality...
February 20, 2018: Proceedings of the National Academy of Sciences of the United States of America
Dhaval Patel, Chuan Xu, Sureshbabu Nagarajan, Zhengchang Liu, Wayne O Hemphill, Runhua Shi, Vladimir N Uversky, Guy A Caldwell, Kim A Caldwell, Stephan N Witt
We probed the role of alpha-synuclein (α-syn) in modulating sorting nexin 3 (Snx3)-retromer-mediated recycling of iron transporters in Saccharomyces cerevisiae and Caenorhabditis elegans. In yeast, the membrane-bound heterodimer Fet3/Ftr1 is the high affinity iron importer. Fet3 is a membrane-bound multicopper ferroxidase, whose ferroxidase domain is orthologous to human ceruloplasmin (Cp), that oxidizes external Fe+2 to Fe+3; the Fe+3 ions then channel through the Ftr1 permease into the cell. When the concentration of external iron is low (< 1 µM), Fet3/Ftr1 is maintained on the plasma membrane by retrograde endocytic-recycling; whereas, when the concentration of external iron is high (> 10 µM), Fet3/Ftr1 is endocytosed and shunted to the vacuole for degradation...
February 14, 2018: Human Molecular Genetics
Yan You, Wan-Zhen Li, Sulin Zhang, Bin Hu, Yue-Xuan Li, Hai-Dong Li, Huan-Huan Tang, Qian-Wen Li, Yun-Yun Guan, Li-Xin Liu, Wei-Lian Bao, Xiaoyan Shen
BACKGROUND & AIMS: Alcoholic liver disease is a major cause of morbidity and mortality worldwide. However, the cellular defense mechanisms underlying ALD are not well understood. Recent studies highlight the involvement of chaperone-mediated autophagy (CMA) in regulating hepatic lipid metabolism. Sorting nexin (SNX) 10 has a regulatory function in endo-lysosomal trafficking and stabilization. Here we investigated the roles of SNX10 in CMA activation and the pathogenesis of alcohol-induced liver injury and steatosis...
February 13, 2018: Journal of Hepatology
Gregor Maschkowitz, Sabine Gärtner, Heike Hofmann-Winkler, Helmut Fickenscher, Michael Winkler
Human cytomegalovirus (HCMV) is a wide-spread human pathogen that causes asymptomatic infection in healthy individuals, but poses a serious threat to immunocompromised patients. During the late phase of HCMV infection, the viral capsid is transported to the cytoplasmic viral assembly center (cVAC) where it is enclosed by the tegument protein layer and the viral envelope. The cVAC consists of circularly arranged vesicles from the trans-Golgi and endosomal networks. The HCMV gene UL35 encodes ppUL35 and its shorter form ppUL35A...
February 14, 2018: Journal of Virology
Shaohua Xu, Saket M Nigam, Lennart Brodin
BACKGROUND: Sorting nexins (SNXs) have diverse functions in protein sorting and membrane trafficking. Recently, single-nucleotide polymorphisms in SNX3 were found to be associated with Alzheimer disease. However, it remains unknown whether SNX3 participates in amyloid (A)β peptide production. OBJECTIVE: To examine the role of SNX3 in Aβ production and APP processing. METHODS: The effect of increased expression of SNX3 was studied in HEK293T cells...
February 7, 2018: Neuro-degenerative Diseases
Wen-Qiang Xia, Yan Liang, Yao Chi, Li-Long Pan, Jing Zhao, Shu-Sheng Liu, Xiao-Wei Wang
Begomoviruses are exclusively transmitted by whiteflies in a persistent circulative manner and cause considerable economic losses to crop production worldwide. Previous studies have shown that begomoviruses accumulate in vesicle-like structures in whitefly midgut cells and that clathrin-mediated endocytosis is responsible for their internalization. However, the process by which begomoviruses are trafficked within whitefly midgut cells remains largely unknown. In this study, we investigated the roles of vesicle trafficking in the transport of Tomato yellow leaf curl virus (TYLCV), a begomovirus that has spread to over 50 countries and caused extensive damage to a range of important crops, within midgut cells of whitefly (Bemisia tabaci)...
January 25, 2018: PLoS Pathogens
Katharina B Beer, Jennifer Rivas-Castillo, Kenneth Kuhn, Gholamreza Fazeli, Birgit Karmann, Jeremy F Nance, Christian Stigloher, Ann M Wehman
Cells release extracellular vesicles (EVs) that mediate intercellular communication and repair damaged membranes. Despite the pleiotropic functions of EVs in vitro, their in vivo function is debated, largely because it is unclear how to induce or inhibit their formation. In particular, the mechanisms of EV release by plasma membrane budding or ectocytosis are poorly understood. We previously showed that TAT-5 phospholipid flippase activity maintains the asymmetric localization of the lipid phosphatidylethanolamine (PE) in the plasma membrane and inhibits EV budding by ectocytosis in Caenorhabditis elegans However, no proteins that inhibit ectocytosis upstream of TAT-5 were known...
January 24, 2018: Proceedings of the National Academy of Sciences of the United States of America
Sulin Zhang, Bin Hu, Yan You, Zhiwen Yang, Lixin Liu, Huanhuan Tang, Weilian Bao, Yunyun Guan, Xiaoyan Shen
Chaperone-mediated autophagy (CMA) characterized by the selective degradation of target proteins has been linked with tumorigenesis in recent years. Here, we explored the function of sorting nexin 10 (SNX10), a protein involved in maintaining endosome/lysosome homeostasis, in mediating CMA activity and its impact on the progression of mouse colorectal cancer. Our results revealed that SNX10 deficiency increased the activation of CMA by preventing the degradation of lysosomal LAMP-2A. In SNX10 KO cells, we disclosed that p21Cip1/WAF1, a master effector in various tumor suppressor pathways, is a substrate of CMA, and decrease of p21Cip1/WAF1 caused by SNX10-mediated CMA activation contributes to HCT116 cell proliferation and survival...
January 17, 2018: Cancer Letters
Mark A Rider, Mujeeb R Cheerathodi, Stephanie N Hurwitz, Dingani Nkosi, Lauren A Howell, Deanna C Tremblay, Xia Liu, Fanxiu Zhu, David G Meckes
Epstein-Barr virus LMP1 is an oncoprotein required for immortalizing B lymphocytes and also plays important roles in transforming non-lymphoid tissue. The discovery of LMP1 protein interactions will likely generate targets to treat EBV-associated cancers. Here, we define the broader LMP1 interactome using the recently developed BioID method. Combined with mass spectrometry, we identified over 1000 proteins across seven independent experiments with direct or indirect relationships to LMP1. Pathway analysis suggests that a significant number of the proteins identified are involved in signal transduction and protein or vesicle trafficking...
January 9, 2018: Virology
Teresa Buenaventura, Nisha Kanda, Phoebe C Douzenis, Ben Jones, Stephen R Bloom, Pauline Chabosseau, Ivan R Corrêa, Domenico Bosco, Lorenzo Piemonti, Piero Marchetti, Paul R Johnson, Am James Shapiro, Guy A Rutter, Alejandra Tomas
The GLP-1 receptor (GLP-1R) is a key target for type 2 diabetes (T2D) treatment. Since endocytic trafficking of agonist-bound receptors is one of the most important routes for regulation of receptor signaling, a better understanding of this process may facilitate the development of new T2D therapeutic strategies. Here, we have screened 29 proteins with known functions in G protein-coupled receptor trafficking for their role in GLP-1R potentiation of insulin secretion in pancreatic beta cells. We identify five (clathrin, dynamin1, AP2, SNX27 and SNX1) that increase and four (HIP1, HIP14, GASP-1 and Nedd4) that decrease insulin secretion from murine insulinoma MIN6B1 cells in response to the GLP-1 analogue exendin-4...
December 28, 2017: Diabetes
Neide Vieira, Carlos Bessa, Ana J Rodrigues, Paulo Marques, Fung-Yi Chan, Ana Xavier de Carvalho, Margarida Correia-Neves, Nuno Sousa
The sorting nexins family of proteins (SNXs) plays pleiotropic functions in protein trafficking and intracellular signaling and has been associated with several disorders, namely Alzheimer's disease and Down's syndrome. Despite the growing association of SNXs with neurodegeneration, not much is known about their function in the nervous system. The aim of this work was to use the nematode Caenorhabditis elegans that encodes in its genome eight SNXs orthologs, to dissect the role of distinct SNXs, particularly in the nervous system...
December 1, 2017: Cellular and Molecular Life Sciences: CMLS
M Tello-Lafoz, C Rodríguez-Rodríguez, G Kinna, L S Loo, W Hong, B M Collins, R D Teasdale, I Mérida
Sorting nexin 27 (SNX27) recycles PSD-95, Dlg1, ZO-1 (PDZ) domain-interacting membrane proteins and is essential to sustain adequate brain functions. Here we define a fundamental SNX27 function in T lymphocytes controlling antigen-induced transcriptional activation and metabolic reprogramming. SNX27 limits the activation of diacylglycerol (DAG)-based signals through its high affinity PDZ-interacting cargo DAG kinase ζ (DGKζ). SNX27 silencing in human T cells enhanced T cell receptor (TCR)-stimulated activator protein 1 (AP-1)- and nuclear factor κB (NF-κB)-mediated transcription...
November 27, 2017: Scientific Reports
Jin Wei, Wei Guo, Huan Lian, Qing Yang, Heng Lin, Shu Li, Hong-Bing Shu
IFNγ is a cytokine that plays a key role in host defense against intracellular pathogens. In addition to the canonical JAK-STAT1 pathway, IFNγ also activates an IKKβ-mediated noncanonical signaling pathway that is essential for induction of a subset of downstream effector genes. The molecular mechanisms and functional significance of this IFNγ-triggered noncanonical pathway remains enigmatic. Here, we identified sorting nexin 8 (SNX8) as an important component of the IFNγ-triggered noncanonical signaling pathway...
December 5, 2017: Proceedings of the National Academy of Sciences of the United States of America
Wen-Ting Lo, Andreja Vujičić Žagar, Fabian Gerth, Martin Lehmann, Dymtro Puchkov, Oxana Krylova, Christian Freund, Leonardo Scapozza, Oscar Vadas, Volker Haucke
Clathrin-mediated endocytosis occurs by bending and remodeling of the membrane underneath the coat. Bin-amphiphysin-rvs (BAR) domain proteins are crucial for endocytic membrane remodeling, but how their activity is spatiotemporally controlled is largely unknown. We demonstrate that the membrane remodeling activity of sorting nexin 9 (SNX9), a late-acting endocytic PX-BAR domain protein required for constriction of U-shaped endocytic intermediates, is controlled by an allosteric structural switch involving coincident detection of the clathrin adaptor AP2 and phosphatidylinositol-3,4-bisphosphate (PI(3,4)P2) at endocytic sites...
November 20, 2017: Developmental Cell
Hana Popelka, Alejandro Damasio, Jenny E Hinshaw, Daniel J Klionsky, Michael J Ragusa
The Atg20 and Snx4/Atg24 proteins have been identified in a screen for mutants defective in a type of selective macroautophagy/autophagy. Both proteins are connected to the Atg1 kinase complex, which is involved in autophagy initiation, and bind phosphatidylinositol-3-phosphate. Atg20 and Snx4 contain putative BAR domains, suggesting a possible role in membrane deformation, but they have been relatively uncharacterized. Here we demonstrate that, in addition to its function in selective autophagy, Atg20 plays a critical role in the efficient induction of nonselective autophagy...
November 21, 2017: Proceedings of the National Academy of Sciences of the United States of America
Antonia A Nemec, Lauren A Howell, Anna K Peterson, Matthew A Murray, Robert J Tomko
Turnover of the 26S proteasome by autophagy is an evolutionarily conserved process that governs cellular proteolytic capacity and eliminates inactive particles. In most organisms, proteasomes are located in both the nucleus and cytoplasm. However, the specific autophagy routes for nuclear and cytoplasmic proteasomes are unclear. Here, we investigate the spatial control of autophagic proteasome turnover in budding yeast (Saccharomyces cerevisiae). We found that nitrogen starvation-induced proteasome autophagy is independent of known nucleophagy pathways, but is compromised when nuclear protein export is blocked...
November 6, 2017: Journal of Biological Chemistry
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