scholarly journals A PX-BAR protein Mvp1/SNX8 and a dynamin-like GTPase Vps1 drive endosomal recycling

2021 ◽  
Author(s):  
Sho W. Suzuki ◽  
Akihiko Oishi ◽  
Nadia Nikulin ◽  
Jeff R. Jorgensen ◽  
Matthew G. Baile ◽  
...  
Keyword(s):  
Membrane Protein ◽  
List Type ◽  
Human Homolog ◽  
Present Evidence ◽  
Endosomal Membrane ◽  
Endosomal Recycling ◽  
Sorting Motif ◽  
Recycling Pathway ◽  
Recycling Systems ◽  
Main Figure

SUMMARYMembrane protein recycling systems are essential for maintenance of the endosome-lysosome system. In yeast, retromer and Snx4 coat complexes are recruited to the endosomal surface where they recognize cargos. They sort cargo and deform the membrane into recycling tubules that bud from the endosome and target to the Golgi. Here, we reveal that the SNX-BAR protein, Mvp1, mediates an endosomal recycling pathway which is mechanistically distinct from the retromer and Snx4 pathways. Mvp1 deforms the endosomal membrane and sorts cargos containing a specific sorting motif into a membrane tubule. Subsequently, Mvp1 recruits the dynamin-like GTPase Vps1 to catalyze membrane scission and release of the recycling tubule. Similarly, SNX8, the human homolog of Mvp1, which has been also implicated in Alzheimer’s disease, mediates formation of an endosomal recycling tubule. Thus, we present evidence for a novel endosomal retrieval pathway that is conserved from yeast to humans.In BriefPX-BAR Mvp1 and dynamin-like GTPase Vps1 drive retromer independent endosomal recycling.HighlightsRetromer- and Snx4-independent endosomal recycling pathway discoveredSNX-BAR Mvp1 and dynamin-like GTPase Vps1 mediate cargo sorting into recycling tubules/vesicles in the absence of retromer functionMvp1 together with retromer and Snx4 complexes contribute to proper endosome functionMvp1 mediated recycling is evolutionary conserved from yeast to humansCharacters: 43,934/45,000 (including spaces and main figure legends but excluding STAR Methods text, supplemental item legends, and References section)

scholarly journals A PX-BAR protein Mvp1/SNX8 and a dynamin-like GTPase Vps1 drive endosomal recycling

eLife ◽  
2021 ◽  
Vol 10 ◽  
Author(s):  
Sho W Suzuki ◽  
Akihiko Oishi ◽  
Nadia Nikulin ◽  
Jeff R Jorgensen ◽  
Matthew G Baile ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Membrane Protein ◽  
Human Homolog ◽  
Present Evidence ◽  
Endosomal Membrane ◽  
Endosomal Recycling ◽  
Sorting Motif ◽  
Recycling Pathway ◽  
Membrane Scission ◽  
Recycling Systems

Membrane protein recycling systems are essential for maintenance of the endosome-lysosome system. In yeast, retromer and Snx4 coat complexes are recruited to the endosomal surface where they recognize cargos. They sort cargo and deform the membrane into recycling tubules that bud from the endosome and target to the Golgi. Here, we reveal that the SNX-BAR protein, Mvp1, mediates an endosomal recycling pathway which is mechanistically distinct from the retromer and Snx4 pathways. Mvp1 deforms the endosomal membrane and sorts cargos containing a specific sorting motif into a membrane tubule. Subsequently, Mvp1 recruits the dynamin-like GTPase Vps1 to catalyze membrane scission and release of the recycling tubule. Similarly, SNX8, the human homolog of Mvp1, which has been also implicated in Alzheimer's disease, mediates formation of an endosomal recycling tubule. Thus, we present evidence for a novel endosomal retrieval pathway that is conserved from yeast to humans.

scholarly journals Regulation of Microtubule-dependent Recycling at the Trans-Golgi Network by Rab6A and Rab6A'

2005 ◽  
Vol 16 (1) ◽  
pp. 162-177 ◽  
Author(s):  
Joanne Young ◽  
Tobias Stauber ◽  
Elaine del Nery ◽  
Isabelle Vernos ◽  
Rainer Pepperkok ◽  
...  
Keyword(s):  
Endoplasmic Reticulum ◽  
Golgi Apparatus ◽  
Small Interfering Rna ◽  
Small Gtpase ◽  
Present Evidence ◽  
Trans Golgi Network ◽  
Endosomal Recycling ◽  
Recycling Pathway ◽  
Golgi Network ◽  
Interfering Rna

The small GTPase rab6A but not the isoform rab6A' has previously been identified as a regulator of the COPI-independent recycling route that carries Golgi-resident proteins and certain toxins from the Golgi to the endoplasmic reticulum (ER). The isoform rab6A' has been implicated in Golgi-to-endosomal recycling. Because rab6A but not A', binds rabkinesin6, this motor protein is proposed to mediate COPI-independent recycling. We show here that both rab6A and rab6A' GTP-restricted mutants promote, with similar efficiency, a microtubule-dependent recycling of Golgi resident glycosylation enzymes upon overexpression. Moreover, we used small interfering RNA mediated down-regulation of rab6A and A' expression and found that reduced levels of rab6 perturbs organization of the Golgi apparatus and delays Golgi-to-ER recycling. Rab6-directed Golgi-to-ER recycling seems to require functional dynactin, as overexpression of p50/dynamitin, or a C-terminal fragment of Bicaudal-D, both known to interact with dynactin inhibit recycling. We further present evidence that rab6-mediated recycling seems to be initiated from the trans-Golgi network. Together, this suggests that a recycling pathway operates at the level of the trans-Golgi linking directly to the ER. This pathway would be the preferred route for both toxins and resident Golgi proteins.

scholarly journals NCU-G1 is a highly glycosylated integral membrane protein of the lysosome

2009 ◽  
Vol 422 (1) ◽  
pp. 83-90 ◽  
Author(s):  
Oliver Schieweck ◽  
Markus Damme ◽  
Bernd Schröder ◽  
Andrej Hasilik ◽  
Bernhard Schmidt ◽  
...  
Keyword(s):  
Amino Acid ◽  
Membrane Proteins ◽  
Membrane Protein ◽  
Mouse Liver ◽  
Lysosomal Membrane ◽  
Molecular Forms ◽  
Type I ◽  
Calculated Molecular Mass ◽  
Sorting Motif ◽  
Lysosomal Membrane Proteins

Until recently, a modest number of approx. 40 lysosomal membrane proteins had been identified and even fewer were characterized in their function. In a proteomic study, using lysosomal membranes from human placenta we identified several candidate lysosomal membrane proteins and proved the lysosomal localization of two of them. In the present study, we demonstrate the lysosomal localization of the mouse orthologue of the human C1orf85 protein, which has been termed kidney-predominant protein NCU-G1 (GenBank® accession number: AB027141). NCU-G1 encodes a 404 amino acid protein with a calculated molecular mass of 39 kDa. The bioinformatics analysis of its amino acid sequence suggests it is a type I transmembrane protein containing a single tyrosine-based consensus lysosomal sorting motif at position 400 within the 12-residue C-terminal tail. Its lysosomal localization was confirmed using immunofluorescence with a C-terminally His-tagged NCU-G1 and the lysosomal marker LAMP-1 (lysosome-associated membrane protein-1) as a reference, and by subcellular fractionation of mouse liver after a tyloxapol-induced density shift of the lysosomal fraction using an anti-NCU-G1 antiserum. In transiently transfected HT1080 and HeLa cells, the His-tagged NCU-G1 was detected in two molecular forms with apparent protein sizes of 70 and 80 kDa, and in mouse liver the endogenous wild-type NCU-G1 was detected as a 75 kDa protein. The remarkable difference between the apparent and the calculated molecular masses of NCU-G1 was shown, by digesting the protein with N-glycosidase F, to be due to an extensive glycosylation. The lysosomal localization was impaired by mutational replacement of an alanine residue for the tyrosine residue within the putative sorting motif.

scholarly journals RABENOSYN separation-of-function mutations uncouple endosomal recycling from lysosomal degradation

2021 ◽  
Author(s):  
Franziska Paul ◽  
Calista Ng ◽  
Shahriar Nafissi ◽  
Yalda Nilipoor ◽  
Ali Reza Tavasoli ◽  
...  
Keyword(s):  
Intellectual Disability ◽  
Exome Sequencing ◽  
Muscle Weakness ◽  
Germline Mutations ◽  
Lysosomal Degradation ◽  
Mendelian Disorder ◽  
Progressive Muscle Weakness ◽  
Endosomal Recycling ◽  
Early Endosomes ◽  
Recycling Pathway

Rabenosyn (RBSN) is a conserved endosomal protein necessary for regulating internalized cargo. Here, we present genetic, cellular and biochemical evidence that two distinct RBSN missense variants are responsible for a novel Mendelian disorder consisting of progressive muscle weakness, facial dysmorphisms, ophthalmoplegia and intellectual disability. Using exome sequencing, we identified recessively-acting germline alleles p.Arg180Gly and p.Gly183Arg which are both situated in the FYVE domain of RBSN. We find that these variants abrogate binding to its cognate substrate PI3P and thus prevent its translocation to early endosomes. Although the endosomal recycling pathway was unaltered, mutant p.Gly183Arg patient fibroblasts exhibit accumulation of cargo tagged for lysosomal degradation. Our results suggest that these variants are separation-of-function alleles, which cause a delay in endosomal maturation without affecting cargo recycling. We conclude that distinct germline mutations in RBSN cause non-overlapping phenotypes with specific and discrete endolysosomal cellular defects.

scholarly journals Twenty-five-year-old woman with palpitations and hypertrophic cardiomyopathy

Heart Asia ◽  
2019 ◽  
Vol 11 (1) ◽  
pp. e011174 ◽  
Author(s):  
Krittapoom Akrawinthawong ◽  
Vineet Kumar
Keyword(s):  
Genetic Testing ◽  
Hypertrophic Cardiomyopathy ◽  
Catheter Ablation ◽  
Membrane Protein ◽  
Similar Condition ◽  
Electrophysiological Study ◽  
Accessory Pathway ◽  
List Type ◽  
Danon Disease ◽  
Unexplained Syncope

Clinical introductionA 25-year-old woman with a diagnosis of hypertrophic cardiomyopathy (HCM) and pre-excitation on ECG presented with unexplained syncope and daily palpitation. Genetic testing was positive for lysosome-associated membrane protein 2 (LAMP2) mutation which confirmed the diagnosis of Danon disease. Her younger sister was diagnosed with a similar condition and received a defibrillator implantation. Her 12-lead ECG (figure 1) and a long strip tracing (figure 2) are shown below.Figure 112-lead ECG.QuestionWhere is the location of the accessory pathway and what is the next appropriate management?Anteroseptal pathway and catheter ablationMid-septal pathway and pacemaker/defibrillator implantationRight lateral pathway and catheter ablationFasciculoventricular pathway and electrophysiological studyLeft lateral pathway and electrophysiological study

In Vivo Internalization of the Somatostatin sst2A Receptor in Rat Brain: Evidence for Translocation of Cell-Surface Receptors into the Endosomal Recycling Pathway

2001 ◽  
Vol 17 (4) ◽  
pp. 646-661 ◽  
Author(s):  
Zsolt Csaba ◽  
Véronique Bernard ◽  
Lone Helboe ◽  
Marie-Thérèse Bluet-Pajot ◽  
Bertrand Bloch ◽  
...  
Keyword(s):  
Cell Surface ◽  
Rat Brain ◽  
Cell Surface Receptors ◽  
Surface Receptors ◽  
Endosomal Recycling ◽  
Recycling Pathway

scholarly journals APEX-based proximity labeling in Plasmodium identifies a membrane protein with dual functions during mosquito infection

2020 ◽  
Author(s):  
Jessica Kehrer ◽  
Dominik Ricken ◽  
Leanne Strauss ◽  
Emma Pietsch ◽  
Julia M. Heinze ◽  
...  
Keyword(s):  
Functional Analysis ◽  
Membrane Protein ◽  
Malaria Parasite ◽  
Model Organism ◽  
Subcellular Fractionation ◽  
Surface Proteins ◽  
List Type ◽  
Proximity Ligation ◽  
C Terminus ◽  
Mosquito Infection

AbstractTransmission of the malaria parasite Plasmodium to mosquitoes necessitates gamete egress from red blood cells to allow zygote formation and ookinete motility to enable penetration of the midgut epithelium. Both processes are dependent on the secretion of proteins from distinct sets of specialized vesicles. Inhibiting some of these proteins has shown potential for blocking parasite transmission to the mosquito. To identify new transmission blocking vaccine candidates, we defined the microneme content from ookinetes of the rodent model organism Plasmodium berghei using APEX2-mediated rapid proximity-dependent biotinylation. Besides known proteins of ookinete micronemes, this identified over 50 novel candidates and sharpened the list of a previous survey based on subcellular fractionation. Functional analysis of a first candidate uncovered a dual role for this membrane protein in male gametogenesis and ookinete midgut traversal. Mutation of a putative trafficking motif in the C-terminus led to its mis-localization in ookinetes and affected ookinete to oocyst transition but not gamete formation. This suggests the existence of distinct functional and transport requirements for Plasmodium proteins in different parasite stages.SignificanceThe genome of the malaria parasite Plasmodium contains over 5500 genes, of which over 30% have no assigned function. Transmission of Plasmodium spp. to the mosquito contains several essential steps that can be inhibited by antibodies or chemical compounds. Yet few proteins involved in these processes are characterized, thus limiting our capacity to generate transmission interfering tools. Here, we establish a method to rapidly identify proteins in a specific compartment within the parasite that is essential for establishment of an infection within the mosquito, and identify over 50 novel candidate proteins. Functional analysis of the top candidate identifies a protein with two independent essential functions in subsequent steps along the Plasmodium life cycle within the mosquito.Highlightsfirst use of APEX based proximity ligation in Apicomplexaidentification of >50 putative ookinete surface proteinsnovel membrane protein essential for microgamete egress and ookinete migrationputative trafficking motif essential in ookinetes but not gametes

scholarly journals Integrin-dependent YAP signaling requires LAMTOR1 mediated delivery of Src to the plasma membrane

2019 ◽  
Author(s):  
Marc R. Block ◽  
Molly Brunner ◽  
Théo Ziegelmeyer ◽  
Dominique Lallemand ◽  
Mylène Pezet ◽  
...  
Keyword(s):  
Cell Periphery ◽  
Matrix Stiffness ◽  
Cell Contractility ◽  
Cellular Processes ◽  
Endosomal Recycling ◽  
Late Endosomes ◽  
Extracellular Matrix Stiffness ◽  
Important Regulator ◽  
Recycling Pathway ◽  
Nuclear Shuttling

AbstractYAP signaling has emerged as an important signaling pathway involved in several normal and pathological processes. While main upstream effectors regulating its activity have been extensively studied, the interplay with other cellular processes has been far less analyzed. Here, we identified the LAMTOR complex as a new important regulator of YAP signaling. We uncovered that p18/LAMTOR1 is required for the recycling of Src on late endosomes to the cell periphery, and consequently to activate a signaling cascade that eventually controls YAP nuclear shuttling. Moreover, p18/LAMTOR1 positives late endosomes distribution is controlled by β1 integrins, extracellular matrix stiffness and cell contractility. This likely relies on the targeting of microtubules to β1 positive focal adhesion via ILK. Altogether our findings identify the late endosomal recycling pathway as a major regulator of YAP.

scholarly journals The VINE complex is a VPS9–domain GEF–containing SNX–BAR coat involved in endosomal sorting

2021 ◽  
Author(s):  
Shawn P Shortill ◽  
Mia S Frier ◽  
Michael Davey ◽  
Elizabeth Conibear
Keyword(s):  
Coat Protein ◽  
Membrane Trafficking ◽  
Protein Sorting ◽  
Vacuolar Membrane ◽  
Membrane Recruitment ◽  
Endosomal Sorting ◽  
Endosomal Recycling ◽  
N Terminus ◽  
Recycling Pathway ◽  
Inactivating Mutation

Membrane trafficking pathways perform important roles in establishing and maintaining the endolysosomal network. Retrograde protein sorting from the endosome is promoted by conserved SNX–BAR–containing coat complexes including retromer which enrich cargo at tubular microdomains and generate transport carriers. In metazoans, retromer cooperates with VARP, a conserved VPS9–domain GEF, to direct an endosomal recycling pathway. The function of the yeast VARP homolog Vrl1 has been overlooked due an inactivating mutation in commonly studied strains. Here, we demonstrate that Vrl1 has features of a SNX–BAR coat protein and forms an obligate complex with Vin1, the paralog of the retromer SNX–BAR protein Vps5. Unique features in the Vin1 N–terminus allow Vrl1 to distinguish it from Vps5, thereby forming what we have named the VINE complex. VINE occupies endosomal tubules and promotes the delivery of a conserved mannose 6–phosphate receptor–like protein to the vacuolar membrane. In addition to sorting functions, membrane recruitment by Vin1 is essential for Vrl1 GEF activity, suggesting that VINE is a multifunctional coat complex that regulates trafficking and signaling events at the endosome.

scholarly journals Golgi membrane protein Erd1 Is essential for recycling a subset of Golgi glycosyltransferases

eLife ◽  
2021 ◽  
Vol 10 ◽  
Author(s):  
Richa Sardana ◽  
Carolyn M Highland ◽  
Beth E Straight ◽  
Christopher F Chavez ◽  
J Christopher Fromme ◽  
...  
Keyword(s):  
Steady State ◽  
Membrane Protein ◽  
Integral Membrane Protein ◽  
Protein Glycosylation ◽  
Sequential Process ◽  
Golgi Membrane ◽  
Present Evidence ◽  
Cytosolic Receptor

Protein glycosylation in the Golgi is a sequential process that requires proper distribution of transmembrane glycosyltransferase enzymes in the appropriate Golgi compartments. Some of the cytosolic machinery required for the steady-state localization of some Golgi enzymes are known but existing models do not explain how many of these enzymes are localized. Here, we uncover the role of an integral membrane protein in yeast, Erd1, as a key facilitator of Golgi glycosyltransferase recycling by directly interacting with both the Golgi enzymes and the cytosolic receptor, Vps74. Loss of Erd1 function results in mislocalization of Golgi enzymes to the vacuole/lysosome. We present evidence that Erd1 forms an integral part of the recycling machinery and ensures productive recycling of several early Golgi enzymes. Our work provides new insights on how the localization of Golgi glycosyltransferases is spatially and temporally regulated, and is finely tuned to the cues of Golgi maturation.

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