scholarly journals Sequence-dependent cargo recognition by SNX-BARs mediates retromer-independent transport of CI-MPR

2017 ◽  
Vol 216 (11) ◽  
pp. 3695-3712 ◽  
Author(s):  
Boris Simonetti ◽  
Chris M. Danson ◽  
Kate J. Heesom ◽  
Peter J. Cullen
Keyword(s):  
Transmembrane Proteins ◽  
Endosomal Sorting ◽  
Sorting Nexin ◽  
Sequence Dependent ◽  
Endosomal Recycling ◽  
Cytosolic Domains ◽  
Sorting Motif ◽  
Golgi Network ◽  
Coupling Sequence

Endosomal recycling of transmembrane proteins requires sequence-dependent recognition of motifs present within their intracellular cytosolic domains. In this study, we have reexamined the role of retromer in the sequence-dependent endosome-to–trans-Golgi network (TGN) transport of the cation-independent mannose 6-phosphate receptor (CI-MPR). Although the knockdown or knockout of retromer does not perturb CI-MPR transport, the targeting of the retromer-linked sorting nexin (SNX)–Bin, Amphiphysin, and Rvs (BAR) proteins leads to a pronounced defect in CI-MPR endosome-to-TGN transport. The retromer-linked SNX-BAR proteins comprise heterodimeric combinations of SNX1 or SNX2 with SNX5 or SNX6 and serve to regulate the biogenesis of tubular endosomal sorting profiles. We establish that SNX5 and SNX6 associate with the CI-MPR through recognition of a specific WLM endosome-to-TGN sorting motif. From validating the CI-MPR dependency of SNX1/2–SNX5/6 tubular profile formation, we provide a mechanism for coupling sequence-dependent cargo recognition with the biogenesis of tubular profiles required for endosome-to-TGN transport. Therefore, the data presented in this study reappraise retromer’s role in CI-MPR transport.

scholarly journals Quantitative high-content imaging identifies novel regulators of Neo1 trafficking at endosomes

2017 ◽  
Vol 28 (11) ◽  
pp. 1539-1550 ◽  
Author(s):  
Lauren E. Dalton ◽  
Björn D. M. Bean ◽  
Michael Davey ◽  
Elizabeth Conibear
Keyword(s):  
Lipid Membrane ◽  
Membrane Asymmetry ◽  
High Content Imaging ◽  
Sorting Nexin ◽  
Binding Partners ◽  
Endosomal Recycling ◽  
Cargo Protein ◽  
Early Endosomes ◽  
Sorting Motif

P4-ATPases are a family of putative phospholipid flippases that regulate lipid membrane asymmetry, which is important for vesicle formation. Two yeast flippases, Drs2 and Neo1, have nonredundant functions in the recycling of the synaptobrevin-like v-SNARE Snc1 from early endosomes. Drs2 activity is needed to form vesicles and regulate its own trafficking, suggesting that flippase activity and localization are linked. However, the role of Neo1 in endosomal recycling is not well characterized. To identify novel regulators of Neo1 trafficking and activity at endosomes, we first identified mutants with impaired recycling of a Snc1-based reporter and subsequently used high-content microscopy to classify these mutants based on the localization of Neo1 or its binding partners, Mon2 and Dop1. This analysis identified a role for Arl1 in stabilizing the Mon2/Dop1 complex and uncovered a new function for Vps13 in early endosome recycling and Neo1 localization. We further showed that the cargo-selective sorting nexin Snx3 is required for Neo1 trafficking and identified an Snx3 sorting motif in the Neo1 N-terminus. Of importance, the Snx3-dependent sorting of Neo1 was required for the correct sorting of another Snx3 cargo protein, suggesting that the incorporation of Neo1 into recycling tubules may influence their formation.

scholarly journals Toward Understanding the Molecular Role of SNX27/Retromer in Human Health and Disease

2021 ◽  
Vol 9 ◽  
Author(s):  
Mintu Chandra ◽  
Amy K. Kendall ◽  
Lauren P. Jackson
Keyword(s):  
Cancer Progression ◽  
Membrane Trafficking ◽  
Endosomal Trafficking ◽  
Channel Trafficking ◽  
Sorting Nexin ◽  
Endosomal Recycling ◽  
Multiple Receptors ◽  
Health And Disease ◽  
Physiological Outcomes

Aberrations in membrane trafficking pathways have profound effects in cellular dynamics of cellular sorting processes and can drive severe physiological outcomes. Sorting nexin 27 (SNX27) is a metazoan-specific sorting nexin protein from the PX-FERM domain family and is required for endosomal recycling of many important transmembrane receptors. Multiple studies have shown SNX27-mediated recycling requires association with retromer, one of the best-known regulators of endosomal trafficking. SNX27/retromer downregulation is strongly linked to Down’s Syndrome (DS) via glutamate receptor dysfunction and to Alzheimer’s Disease (AD) through increased intracellular production of amyloid peptides from amyloid precursor protein (APP) breakdown. SNX27 is further linked to addiction via its role in potassium channel trafficking, and its over-expression is linked to tumorigenesis, cancer progression, and metastasis. Thus, the correct sorting of multiple receptors by SNX27/retromer is vital for normal cellular function to prevent human diseases. The role of SNX27 in regulating cargo recycling from endosomes to the cell surface is firmly established, but how SNX27 assembles with retromer to generate tubulovesicular carriers remains elusive. Whether SNX27/retromer may be a putative therapeutic target to prevent neurodegenerative disease is now an emerging area of study. This review will provide an update on our molecular understanding of endosomal trafficking events mediated by the SNX27/retromer complex on endosomes.

Retromer and sorting nexins in endosomal sorting

2015 ◽  
Vol 43 (1) ◽  
pp. 33-47 ◽  
Author(s):  
Matthew Gallon ◽  
Peter J. Cullen
Keyword(s):  
Plasma Membrane ◽  
Present Article ◽  
Transmembrane Proteins ◽  
Molecular Architecture ◽  
Sorting Nexins ◽  
Endosomal Sorting ◽  
Sorting Nexin ◽  
Cargo Proteins ◽  
Associated Proteins ◽  
Lysosome Related Organelles

The evolutionarily conserved endosomal retromer complex rescues transmembrane proteins from the lysosomal degradative pathway and facilitates their recycling to other cellular compartments. Retromer functions in conjunction with numerous associated proteins, including select members of the sorting nexin (SNX) family. In the present article, we review the molecular architecture and cellular roles of retromer and its various functional partners. The endosomal network is a crucial hub in the trafficking of proteins through the cellular endomembrane system. Transmembrane proteins, here termed cargos, enter endosomes by endocytosis from the plasma membrane or by trafficking from the trans-Golgi network (TGN). Endosomal cargo proteins face one of the two fates: retention in the endosome, leading ultimately to lysosomal degradation or export from the endosome for reuse (‘recycling’). The balance of protein degradation and recycling is crucial to cellular homoeostasis; inappropriate sorting of proteins to either fate leads to cellular dysfunction. Retromer is an endosome-membrane-associated protein complex central to the recycling of many cargo proteins from endosomes, both to the TGN and the plasma membrane (and other specialized compartments, e.g. lysosome-related organelles). Retromer function is reliant on a number of proteins from the SNX family. In the present article, we discuss this inter-relationship and how defects in retromer function are increasingly being linked with human disease.

scholarly journals The emerging role of sorting nexins in cardiovascular diseases

2019 ◽  
Vol 133 (5) ◽  
pp. 723-737 ◽  
Author(s):  
Jian Yang ◽  
Van Anthony M. Villar ◽  
Selim Rozyyev ◽  
Pedro A. Jose ◽  
Chunyu Zeng
Keyword(s):  
Protein Trafficking ◽  
Current Knowledge ◽  
Endocytic Pathway ◽  
Regulatory Mechanisms ◽  
Diverse Group ◽  
Sorting Nexins ◽  
Endosomal Sorting ◽  
Sorting Nexin ◽  
Endosomal Signaling

AbstractThe sorting nexin (SNX) family consists of a diverse group of cytoplasmic- and membrane-associated phosphoinositide-binding proteins that play pivotal roles in the regulation of protein trafficking. This includes the entire endocytic pathway, such as endocytosis, endosomal sorting, and endosomal signaling. Dysfunctions of SNX pathway are involved in several forms of cardiovascular disease (CVD). Moreover, SNX gene variants are associated with CVDs. In this review, we discuss the current knowledge on SNX-mediated regulatory mechanisms and their roles in the pathogenesis and treatment of CVDs.

scholarly journals Adaptor proteins involved in polarized sorting

2014 ◽  
Vol 204 (1) ◽  
pp. 7-17 ◽  
Author(s):  
Juan S. Bonifacino
Keyword(s):  
Epithelial Cells ◽  
Transmembrane Proteins ◽  
Adaptor Protein ◽  
Adaptor Proteins ◽  
Coat Proteins ◽  
Membrane Domains ◽  
Recycling Endosomes ◽  
Polarized Cells ◽  
Cytosolic Domains ◽  
Golgi Network

Polarized cells such as epithelial cells and neurons exhibit different plasma membrane domains with distinct protein compositions. Recent studies have shown that sorting of transmembrane proteins to the basolateral domain of epithelial cells and the somatodendritic domain of neurons is mediated by recognition of signals in the cytosolic domains of the proteins by adaptors. These adaptors are components of protein coats associated with the trans-Golgi network and/or recycling endosomes. The clathrin-associated adaptor protein 1 (AP-1) complex plays a preeminent role in this process, although other adaptors and coat proteins, such as AP-4, ARH, Numb, exomer, and retromer, have also been implicated.

scholarly journals The role of VPS4 in ESCRT-III polymer remodeling

2019 ◽  
Vol 47 (1) ◽  
pp. 441-448 ◽  
Author(s):  
Christophe Caillat ◽  
Sourav Maity ◽  
Nolwenn Miguet ◽  
Wouter H. Roos ◽  
Winfried Weissenhorn
Keyword(s):  
Active Role ◽  
Mechanistic Models ◽  
Membrane Remodeling ◽  
Filament Formation ◽  
Enveloped Viruses ◽  
Endosomal Sorting ◽  
Membrane Fission ◽  
Dynamic Assembly ◽  
Inside Out

Abstract The endosomal sorting complex required for transport-III (ESCRT-III) and VPS4 catalyze a variety of membrane-remodeling processes in eukaryotes and archaea. Common to these processes is the dynamic recruitment of ESCRT-III proteins from the cytosol to the inner face of a membrane neck structure, their activation and filament formation inside or at the membrane neck and the subsequent or concomitant recruitment of the AAA-type ATPase VPS4. The dynamic assembly of ESCRT-III filaments and VPS4 on cellular membranes induces constriction of membrane necks with large diameters such as the cytokinetic midbody and necks with small diameters such as those of intraluminal vesicles or enveloped viruses. The two processes seem to use different sets of ESCRT-III filaments. Constriction is then thought to set the stage for membrane fission. Here, we review recent progress in understanding the structural transitions of ESCRT-III proteins required for filament formation, the functional role of VPS4 in dynamic ESCRT-III assembly and its active role in filament constriction. The recent data will be discussed in the context of different mechanistic models for inside-out membrane fission.

scholarly journals Lysosomal Hydrolase Mannose 6-Phosphate Uncovering Enzyme Resides in the trans-Golgi Network

2001 ◽  
Vol 12 (6) ◽  
pp. 1623-1631 ◽  
Author(s):  
Jack Rohrer ◽  
Rosalind Kornfeld
Keyword(s):  
Plasma Membrane ◽  
Fluorescent Protein ◽  
Lysosomal Hydrolases ◽  
Intracellular Location ◽  
Trans Golgi Network ◽  
Cytosolic Domain ◽  
Cytosolic Domains ◽  
Mannose 6 Phosphate ◽  
Green Fluorescent ◽  
Golgi Network

A crucial step in lysosomal biogenesis is catalyzed by “uncovering” enzyme (UCE), which removes a coveringN-acetylglucosamine from the mannose 6-phosphate (Man-6-P) recognition marker on lysosomal hydrolases. This study shows that UCE resides in the trans-Golgi network (TGN) and cycles between the TGN and plasma membrane. The cytosolic domain of UCE contains two potential endocytosis motifs: 488YHPL and C-terminal 511NPFKD. YHPL is shown to be the more potent of the two in retrieval of UCE from the plasma membrane. A green-fluorescent protein-UCE transmembrane-cytosolic domain fusion protein colocalizes with TGN 46, as does endogenous UCE in HeLa cells, showing that the transmembrane and cytosolic domains determine intracellular location. These data imply that the Man-6-P recognition marker is formed in the TGN, the compartment where Man-6-P receptors bind cargo and are packaged into clathrin-coated vesicles.

scholarly journals A dileucine signal situated in the C-terminal tail of the lysosomal membrane protein p40 is responsible for its targeting to lysosomes

2008 ◽  
Vol 414 (3) ◽  
pp. 431-440 ◽  
Author(s):  
Marielle Boonen ◽  
Roberta Rezende de Castro ◽  
Gaëlle Cuvelier ◽  
Isabelle Hamer ◽  
Michel Jadot
Keyword(s):  
Subcellular Fractionation ◽  
Lysosomal Membrane ◽  
Consensus Sequences ◽  
Cell Surface Biotinylation ◽  
Dileucine Motif ◽  
Lysosomal Sorting ◽  
Critical Residues ◽  
Lysosomal Membrane Proteins ◽  
Golgi Network

Transport of newly synthesized lysosomal membrane proteins from the TGN (trans-Golgi network) to the lysosomes is due to the presence of specific signals in their cytoplasmic domains that are recognized by cytosolic adaptors. p40, a hypothetical transporter of 372 amino acids localized in the lysosomal membrane, contains four putative lysosomal sorting motifs in its sequence: three of the YXXϕ-type (Y6QLF, Y106VAL, Y333NGL) and one of the [D/E]XXXL[L/I]-type (EQERL360L361). To test the role of these motifs in the biosynthetic transport of p40, we replaced the most critical residues of these consensus sequences, the tyrosine residue or the leucine–leucine pair, by alanine or alanine–valine respectively. We analysed the subcellular localization of the mutated p40 proteins in transfected HeLa cells by confocal microscopy and by biochemical approaches (subcellular fractionation on self-forming Percoll density gradients and cell surface biotinylation). The results of the present study show that p40 is mistargeted to the plasma membrane when its dileucine motif is disrupted. No role of the tyrosine motifs could be put forward. Taken together, our results provide evidence that the sorting of p40 from the TGN to the lysosomes is directed by the dileucine EQERL360L361 motif situated in its C-terminal tail.

A Regulatory Role of the Endosomal Sorting Machinery in Controlling Plasma LDL Cholesterol Levels and Atherosclerosis in Mice and Humans

2018 ◽  
Vol 32 ◽  
pp. 18
Author(s):  
Melinde Wijers ◽  
Antoine Rimbert ◽  
Nawar Dalila ◽  
Alina Fedoseienko ◽  
Karin Wolters ◽  
...  
Keyword(s):  
Ldl Cholesterol ◽  
Regulatory Role ◽  
Endosomal Sorting ◽  
Cholesterol Levels
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