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 Retromer is involved in epithelial Na+ channel trafficking

2020 ◽  
Vol 319 (5) ◽  
pp. F895-F907 ◽  
Author(s):  
Tanya T. Cheung ◽  
Anna C. Geda ◽  
Adam W. Ware ◽  
Sahib R. Rasulov ◽  
Polly Tenci ◽  
...  
Keyword(s):  
Plasma Membrane ◽  
Cell Surface ◽  
Early Endosome ◽  
Na Channel ◽  
Channel Trafficking ◽  
Sorting Nexin ◽  
Rate Limiting Step ◽  
Surface Population ◽  
Complex Protein ◽  
Associated Proteins

The epithelial Na+ channel (ENaC) located at the apical membrane in many epithelia is the rate-limiting step for Na+ reabsorption. Tight regulation of the plasma membrane population of ENaC is required, as hypertension or hypotension may result if too many or too few ENaCs are present. Endocytosed ENaC travels to the early endosome and is then either trafficked to the lysosome for degradation or recycled back to the plasma membrane. Recently, the retromer recycling complex, located at the early endosome, has been implicated in plasma membrane protein recycling pathways. We hypothesized that the retromer is required for recycling of ENaC. Stabilization of retromer function with the retromer stabilizing chaperone R55 increased ENaC current, whereas knockdown or overexpression of individual retromer and associated proteins altered ENaC current and cell surface population of ENaC. KIBRA was identified as an ENaC-binding protein allowing ENaC to link to sorting nexin 4 to alter ENaC trafficking. Knockdown of the retromer-associated cargo-binding sorting nexin 27 protein did not alter ENaC current, whereas CCDC22, a CCC-complex protein, coimmunoprecipitated with ENaC, and CCDC22 knockdown decreased ENaC current and population at the cell surface. Together, our results confirm that retromer and the CCC complex play a role in recycling of ENaC to the plasma membrane.

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.

ESCRT-mediated sorting and intralumenal vesicle concatenation in plants

2018 ◽  
Vol 46 (3) ◽  
pp. 537-545 ◽  
Author(s):  
Marisa S. Otegui
Keyword(s):  
Plasma Membrane ◽  
Membrane Proteins ◽  
Endocytic Pathway ◽  
Endosomal Sorting ◽  
Evolutionary Diversification ◽  
Escrt Machinery ◽  
Membrane Fission ◽  
Associated Proteins

The degradation of plasma membrane and other membrane-associated proteins require their sorting at endosomes for delivery to the vacuole. Through the endocytic pathway, ubiquitinated membrane proteins (cargo) are delivered to endosomes where the ESCRT (endosomal sorting complex required for transport) machinery sorts them into intralumenal vesicles for degradation. Plants contain both conserved and plant-specific ESCRT subunits. In this review, I discuss the role of characterized plant ESCRT components, the evolutionary diversification of the plant ESCRT machinery, and a recent study showing that endosomal intralumenal vesicles form in clusters of concatenated vesicle buds by temporally uncoupling membrane constriction from membrane fission.

scholarly journals Identification of an inhibitory budding signal that blocks the release of HIV particles and exosome/microvesicle proteins

2011 ◽  
Vol 22 (6) ◽  
pp. 817-830 ◽  
Author(s):  
Xin Gan ◽  
Stephen J. Gould
Keyword(s):  
Plasma Membrane ◽  
Plasma Membranes ◽  
Animal Cells ◽  
Virus Budding ◽  
Gag Protein ◽  
Endosomal Sorting ◽  
Escrt Machinery ◽  
Cargo Delivery ◽  
Immunodeficiency Virus ◽  
Cargo Proteins

 Animal cells bud exosomes and microvesicles (EMVs) from endosome and plasma membranes. The combination of higher-order oligomerization and plasma membrane binding is a positive budding signal that targets diverse proteins into EMVs and retrovirus particles. Here we describe an inhibitory budding signal (IBS) from the human immunodeficiency virus (HIV) Gag protein. This IBS was identified in the spacer peptide 2 (SP2) domain of Gag, is activated by C-terminal exposure of SP2, and mediates the severe budding defect of p6-deficient and PTAP-deficient strains of HIV. This IBS also impairs the budding of CD63 and several other viral and nonviral EMV proteins. The IBS does not prevent cargo delivery to the plasma membrane, a major site of EMV and virus budding. However, the IBS does inhibit an interaction between EMV cargo proteins and VPS4B, a component of the endosomal sorting complexes required for transport (ESCRT) machinery. Taken together, these results demonstrate that inhibitory signals can block protein and virus budding, raise the possibility that the ESCRT machinery plays a role in EMV biogenesis, and shed new light on the role of the p6 domain and PTAP motif in the biogenesis of HIV particles.

scholarly journals Microtubule-dependent endosomal sorting of clathrin-independent cargo by Hook1

2013 ◽  
Vol 201 (2) ◽  
pp. 233-247 ◽  
Author(s):  
Lymarie Maldonado-Báez ◽  
Nelson B. Cole ◽  
Helmut Krämer ◽  
Julie G. Donaldson
Keyword(s):  
Plasma Membrane ◽  
Major Histocompatibility Complex ◽  
Cell Spreading ◽  
Complex Class ◽  
Present Evidence ◽  
Endosomal Sorting ◽  
Histocompatibility Complex ◽  
Cargo Protein ◽  
Cargo Proteins ◽  
Bulk Membrane

Many plasma membrane (PM) proteins enter cells nonselectively through clathrin-independent endocytosis (CIE). Here, we present evidence that cytoplasmic sequences in three CIE cargo proteins—CD44, CD98, and CD147—were responsible for the rapid sorting of these proteins into endosomal tubules away from endosomes associated with early endosomal antigen 1 (EEA1). We found that Hook1, a microtubule- and cargo-tethering protein, recognized the cytoplasmic tail of CD147 to help sort it and CD98 into Rab22a-dependent tubules associated with recycling. Depletion of Hook1 from cells altered trafficking of CD44, CD98, and CD147 toward EEA1 compartments and impaired the recycling of CD98 back to the PM. In contrast, another CIE cargo protein, major histocompatibility complex class I, which normally traffics to EEA1 compartments, was not affected by depletion of Hook1. Loss of Hook1 also led to an inhibition of cell spreading, implicating a role for Hook1 sorting of specific CIE cargo proteins away from bulk membrane and back to the PM.

scholarly journals Grd19/Snx3p functions as a cargo-specific adapter for retromer-dependent endocytic recycling

2007 ◽  
Vol 177 (1) ◽  
pp. 115-125 ◽  
Author(s):  
Todd I. Strochlic ◽  
Thanuja Gangi Setty ◽  
Anand Sitaram ◽  
Christopher G. Burd
Keyword(s):  
Plasma Membrane ◽  
Golgi Apparatus ◽  
Rab Gtpase ◽  
Endocytic Recycling ◽  
Sorting Nexins ◽  
Sorting Nexin ◽  
Retromer Complex ◽  
Iron Transporter ◽  
Endocytic Sorting ◽  
Recycling Pathway

Amajor function of the endocytic system is the sorting of cargo to various organelles. Endocytic sorting of the yeast reductive iron transporter, which is composed of the Fet3 and Ftr1 proteins, is regulated by available iron. When iron is provided to iron-starved cells, Fet3p–Ftr1p is targeted to the lysosome-like vacuole and degraded. In contrast, when iron is not available, Fet3p–Ftr1p is maintained on the plasma membrane via an endocytic recycling pathway requiring the sorting nexin Grd19/Snx3p, the pentameric retromer complex, and the Ypt6p Golgi Rab GTPase module. A recycling signal in Ftr1p was identified and found to bind directly to Grd19/Snx3p. Retromer and Grd19/Snx3p partially colocalize to tubular endosomes, where they are physically associated. After export from the endosome, Fet3p–Ftr1p transits through the Golgi apparatus for resecretion. Thus, Grd19/Snx3p, functions as a cargo-specific adapter for the retromer complex, establishing a precedent for a mechanism by which sorting nexins expand the repertoire of retromer-dependent cargos.

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 Sorting nexin 27 regulates basal and stimulated brush border trafficking of NHE3

2015 ◽  
Vol 26 (11) ◽  
pp. 2030-2043 ◽  
Author(s):  
Varsha Singh ◽  
Jianbo Yang ◽  
Boyoung Cha ◽  
Tiane-e Chen ◽  
Rafiquel Sarker ◽  
...  
Keyword(s):  
Plasma Membrane ◽  
Epithelial Cells ◽  
Pdz Domain ◽  
Surface Expression ◽  
Dependent Manner ◽  
Intestinal Epithelial ◽  
Pdz Domains ◽  
Sorting Nexin ◽  
C Terminus ◽  
Cargo Proteins

Sorting nexin 27 (SNX27) contains a PDZ domain that is phylogenetically related to the PDZ domains of the NHERF proteins. Studies on nonepithelial cells have shown that this protein is located in endosomes, where it regulates trafficking of cargo proteins in a PDZ domain–dependent manner. However, the role of SNX27 in trafficking of cargo proteins in epithelial cells has not been adequately explored. Here we show that SNX27 directly interacts with NHE3 (C-terminus) primarily through the SNX27 PDZ domain. A combination of knockdown and reconstitution experiments with wild type and a PDZ domain mutant (GYGF → GAGA) of SNX27 demonstrate that the PDZ domain of SNX27 is required to maintain basal NHE3 activity and surface expression of NHE3 in polarized epithelial cells. Biotinylation-based recycling and degradation studies in intestinal epithelial cells show that SNX27 is required for the exocytosis (not endocytosis) of NHE3 from early endosome to plasma membrane. SNX27 is also required to regulate the retention of NHE3 on the plasma membrane. The findings of the present study extend our understanding of PDZ-mediated recycling of cargo proteins from endosome to plasma membrane in epithelial cells.

scholarly journals Membrane manipulations by the ESCRT machinery

F1000Research ◽  
2015 ◽  
Vol 4 ◽  
pp. 516 ◽  
Author(s):  
Greg Odorizzi
Keyword(s):  
Plasma Membrane ◽  
Transmembrane Proteins ◽  
Membrane Dynamics ◽  
Endocytic Pathway ◽  
Current Understanding ◽  
Eukaryotic Cells ◽  
Major Research ◽  
Endosomal Sorting ◽  
Escrt Machinery ◽  
Research Findings

The endosomal sorting complexes required for transport (ESCRTs) collectively comprise a machinery that was first known for its function in the degradation of transmembrane proteins in the endocytic pathway of eukaryotic cells. Since their discovery, however, ESCRTs have been recognized as playing important roles at the plasma membrane, which appears to be the original site of function for the ESCRT machinery. This article reviews some of the major research findings that have shaped our current understanding of how the ESCRT machinery controls membrane dynamics and considers new roles for the ESCRT machinery that might be driven by these mechanisms.

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