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Yuantai Wu, Mehmet Takar, Andrea A Cuentas-Condori, Todd R Graham
NEO1 is an essential gene in budding yeast and belongs to a highly conserved subfamily of P-type ATPase genes that encode phospholipid flippases. Inactivation of temperature sensitive neo1(ts) alleles produces pleiomorphic defects in the secretory and endocytic pathways, including fragmented vacuoles. A screen for multicopy suppressors of neo1-2(ts) growth defects yielded YPT7, which encodes a Rab7 homolog involved in SNARE-dependent vacuolar fusion. YPT7 suppressed the vacuole fragmentation phenotype of neo1-2, but did not suppress Golgi-associated protein trafficking defects...
July 2016: Cellular Logistics
Jie Yin, Xiaocui Liu, Qing He, Lujun Zhou, Zengqiang Yuan, Siqi Zhao
Triggering receptor expressed on myeloid cells 2 (Trem2), an immune-modulatory receptor, is preferentially expressed in microglia of central nervous system. Trem2 might be involved in the development of Alzheimer's disease through regulating the inflammatory responses and phagocytosis of microglia. However, the intracellular trafficking of Trem2 remains unclear. In this study, we showed that Trem2 in the plasma membrane underwent endocytosis and recycling. Trem2 is internalized in a clathrin-dependent manner and then recycled back to the plasma membrane through Vps35, the key component of cargo recognition core of retromer complex, but not Rab11...
September 26, 2016: Traffic
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
Catherine M Buckley, Navin Gopaldass, Cristina Bosmani, Simon A Johnston, Thierry Soldati, Robert H Insall, Jason S King
Macropinocytosis is an ancient mechanism that allows cells to harvest nutrients from extracellular media, which also allows immune cells to sample antigens from their surroundings. During macropinosome formation, bulk plasma membrane is internalized with all its integral proteins. It is vital for cells to salvage these proteins before degradation, but the mechanisms for sorting them are not known. Here we describe the evolutionarily conserved recruitment of the WASH (WASP and SCAR homolog) complex to both macropinosomes and phagosomes within a minute of internalization...
October 4, 2016: Proceedings of the National Academy of Sciences of the United States of America
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
Mohammed M Nooh, Salvatore Mancarella, Suleiman W Bahouth
ß1-adrenergic receptor (ß1-AR) agonists and antagonists are widely used in the treatment of major cardiovascular diseases such as heart failure and hypertension. The ß1-AR like other G protein-couple receptors (GPCR) is endocytosed in response to intense agonist activation. Recycling of the agonist-internalized ß1-AR is dependent on its carboxy-terminal type-1 PSD-95/DLG/ZO1 (PDZ) and on phospho-serine(312) in the third intracellular loop of the ß1-AR. Progressive elongation of the ß1-AR at its C-tail inactivated the PDZ-biding domain and inhibited the recycling of the ß1-AR...
September 16, 2016: Biochemical Pharmacology
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
Kate Harrison, Ismar R Haga, Tali Pechenick Jowers, Seema Jasim, Jean-Christophe Cintrat, Daniel Gillet, Thomas Schmitt-John, Paul Digard, Philippa M Beard
: Poxviruses such as Vaccinia virus (VACV) undertake a complex cytoplasmic replication cycle which involves morphogenesis through four distinct virion forms, and includes a crucial "wrapping" step whereby intracellular mature virions (IMVs) are wrapped in two additional membranes to form intracellular enveloped virions (IEVs). To determine if cellular retrograde transport pathways were required for this wrapping step we examined VACV morphogenesis in cells with reduced expression of the tetrameric tethering factor complex GARP (Golgi-associated retrograde pathway complex), a central component of retrograde transport...
August 31, 2016: Journal of Virology
Anindita Bose, M Flint Beal
Parkinson's disease (PD) is the second most common neurodegenerative disease. About 2% of the population above the age of 60 is affected by the disease. The pathological hallmarks of the disease include the loss of dopaminergic neurons in the substantia nigra and the presence of Lewy bodies that are made of α-synuclein. Several theories have been suggested for the pathogenesis of PD, of which mitochondrial dysfunction plays a pivotal role in both sporadic and familial forms of the disease. Dysfunction of the mitochondria that is caused by bioenergetic defects, mutations in mitochondrial DNA, nuclear DNA gene mutations linked to mitochondria, and changes in dynamics of the mitochondria such fusion or fission, changes in size and morphology, alterations in trafficking or transport, altered movement of mitochondria, impairment of transcription, and the presence of mutated proteins associated with mitochondria are implicated in PD...
October 2016: Journal of Neurochemistry
Kirsty J McMillan, Matthew Gallon, Adam P Jellett, Thomas Clairfeuille, Frances C Tilley, Ian McGough, Chris M Danson, Kate J Heesom, Kevin A Wilkinson, Brett M Collins, Peter J Cullen
The retromer complex acts as a scaffold for endosomal protein complexes that sort integral membrane proteins to various cellular destinations. The retromer complex is a heterotrimer of VPS29, VPS35, and VPS26. Two of these paralogues, VPS26A and VPS26B, are expressed in humans. Retromer dysfunction is associated with neurodegenerative disease, and recently, three VPS26A mutations (p.K93E, p.M112V, and p.K297X) were discovered to be associated with atypical parkinsonism. Here, we apply quantitative proteomics to provide a detailed description of the retromer interactome...
August 15, 2016: Journal of Cell Biology
Mo Zhou, Heidi Wiener, Wenjuan Su, Yong Zhou, Caroline Liot, Ian Ahearn, John F Hancock, Mark R Philips
Ras guanosine triphosphatases (GTPases) regulate signaling pathways only when associated with cellular membranes through their C-terminal prenylated regions. Ras proteins move between membrane compartments in part via diffusion-limited, fluid phase transfer through the cytosol, suggesting that chaperones sequester the polyisoprene lipid from the aqueous environment. In this study, we analyze the nature of the pool of endogenous Ras proteins found in the cytosol. The majority of the pool consists of farnesylated, but not palmitoylated, N-Ras that is associated with a high molecular weight (HMW) complex...
August 15, 2016: Journal of Cell Biology
Chen Wang, Mengxi Niu, Zehua Zhou, Xiaoyuan Zheng, Lingzhi Zhang, Ye Tian, Xiaojun Yu, Guojun Bu, Huaxi Xu, Qilin Ma, Yun-Wu Zhang
Vacuolar protein sorting 35 (VPS35) is a retromer complex component regulating membrane protein trafficking and retrieval. Mutations or dysfunction of VPS35 have been linked to Parkinson's disease (PD), which is pathologically characterized by the loss of dopamine neurons in brain substantia nigra region. Dopamine plays a key role in regulating various brain physiological functions by binding to its receptors and triggering their endocytosis and signaling pathways. However, it is unclear whether there is a link between VPS35 and dopamine signaling in PD...
October 2016: Neurobiology of Aging
Rui Dong, Yasunori Saheki, Sharan Swarup, Louise Lucast, J Wade Harper, Pietro De Camilli
VAP (VAPA and VAPB) is an evolutionarily conserved endoplasmic reticulum (ER)-anchored protein that helps generate tethers between the ER and other membranes through which lipids are exchanged across adjacent bilayers. Here, we report that by regulating PI4P levels on endosomes, VAP affects WASH-dependent actin nucleation on these organelles and the function of the retromer, a protein coat responsible for endosome-to-Golgi traffic. VAP is recruited to retromer budding sites on endosomes via an interaction with the retromer SNX2 subunit...
July 14, 2016: Cell
Jordan Follett, Andrea Bugarcic, Zhe Yang, Nicholas Ariotti, Suzanne J Norwood, Brett M Collins, Robert G Parton, Rohan D Teasdale
Endosomal sorting is a highly orchestrated cellular process. Retromer is a heterotrimeric complex that associates with endosomal membranes and facilitates the retrograde sorting of multiple receptors, including the cation-independent mannose 6-phosphate receptor for lysosomal enzymes. The cycling of retromer on and off the endosomal membrane is regulated by a network of retromer-interacting proteins. Here, we find that Parkinson disease-associated Vps35 variant, R524W, but not P316S, is a loss-of-function mutation as marked by a reduced association with this regulatory network and dysregulation of endosomal receptor sorting...
August 26, 2016: Journal of Biological Chemistry
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
Lei Xiong, Wen-Fang Xia, Fu-Lei Tang, Jin-Xiu Pan, Lin Mei, Wen-Cheng Xiong
Parathyroid hormone (PTH) plays critical, but distinct, roles in bone remodeling, including bone formation (anabolic response) and resorption (catabolic response). Although its signaling and function have been extensively investigated, it just began to be understood how distinct functions are induced by PTH activating a common receptor, the PTH type 1 receptor (PTH1R), and how PTH1R signaling is terminated. Here, we provide evidence for vacuolar protein sorting 35 (VPS35), a major component of retromer, in regulating PTH1R trafficking, turning off PTH signaling, and promoting its catabolic function...
July 2016: EBioMedicine
Veronica Meraviglia, Alessandro Francesco Ulivi, Marta Boccazzi, Fabiola Valenza, Alessandra Fratangeli, Maria Passafaro, Davide Lecca, Fiorenza Stagni, Andrea Giacomini, Renata Bartesaghi, Maria P Abbracchio, Stefania Ceruti, Patrizia Rosa
The G protein-coupled receptor 17 (GPR17) plays crucial roles in myelination. It is highly expressed during transition of oligodendrocyte progenitor cells to immature oligodendrocytes, but, after this stage, it must be down-regulated to allow generation of mature myelinating cells. After endocytosis, GPR17 is sorted into lysosomes for degradation or recycled to the plasma membrane. Balance between degradation and recycling is important for modulation of receptor levels at the cell surface and thus for the silencing/activation of GPR17-signaling pathways that, in turn, affect oligodendrocyte differentiation...
August 2016: Glia
Nadine Sowada, Barbara Stiller, Christian Kubisch
The Saccharomyces cerevisiae gene VPS35 encodes a component of the retromer complex which is involved in vesicle transport from endosomes to the trans-Golgi network. Yeast and human VPS35 orthologs are highly conserved and mutations in human VPS35 cause an autosomal dominant form of late-onset Parkinson disease (PD). We now show that deletion of VPS35 in yeast (vps35Δ) leads to a dose-dependent growth defect towards copper. This increased sensitivity could be rescued by transformation with yeast wild-type VPS35 but not by the expression of a construct harboring the yeast equivalent (i...
August 5, 2016: Biochemical and Biophysical Research Communications
David G Robinson, Jean-Marc Neuhaus
To prevent their being released to the cell exterior, acid hydrolases are recognized by receptors at some point in the secretory pathway and diverted towards the lytic compartment of the cell (lysosome or vacuole). In animal cells, the receptor is called the mannosyl 6-phosphate receptor (MPR) and it binds hydrolase ligands in the trans-Golgi network (TGN). These ligands are then sequestered into clathrin-coated vesicles (CCVs) because of motifs in the cytosolic tail of the MPR which interact first with monomeric adaptors (Golgi-localized, Gamma-ear-containing, ARF-binding proteins, GGAs) and then with tetrameric (adaptin) adaptor complexes...
August 2016: Journal of Experimental Botany
Olivia L McGovern, Vern B Carruthers
How the protozoan pathogen Toxoplasma gondii and related parasites shuttle proteins through their intricate system of endomembranous compartments remains unclear. Sangaré et al. show that the Toxoplasma retromer complex is essential for parasite viability through its role in protein targeting to multiple locales and its interactions with newly identified partners.
May 27, 2016: Trends in Parasitology
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