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Frontiers in Cellular and Infection... 2019
Topics: Bacteria; Bacterial Proteins; Bacterial Secretion Systems; Host-Pathogen Interactions; Membrane Transport Proteins; Protein Transport
PubMed: 32039049
DOI: 10.3389/fcimb.2019.00473 -
The Journal of Biological Chemistry Jul 2022An ever-increasing number of proteins have been shown to translocate across various membranes of bacterial as well as eukaryotic cells in their folded states as a part... (Review)
Review
An ever-increasing number of proteins have been shown to translocate across various membranes of bacterial as well as eukaryotic cells in their folded states as a part of physiological and/or pathophysiological processes. Herein, we provide an overview of the systems/processes that are established or likely to involve the membrane translocation of folded proteins, such as protein export by the twin-arginine translocation system in bacteria and chloroplasts, unconventional protein secretion and protein import into the peroxisome in eukaryotes, and the cytosolic entry of proteins (e.g., bacterial toxins) and viruses into eukaryotes. We also discuss the various mechanistic models that have previously been proposed for the membrane translocation of folded proteins including pore/channel formation, local membrane disruption, membrane thinning, and transport by membrane vesicles. Finally, we introduce a newly discovered vesicular transport mechanism, vesicle budding and collapse, and present evidence that vesicle budding and collapse may represent a unifying mechanism that drives some (and potentially all) of folded protein translocation processes.
Topics: Bacteria; Bacterial Proteins; Eukaryota; Membrane Transport Proteins; Peroxisomes; Protein Folding; Protein Sorting Signals; Protein Transport; Twin-Arginine-Translocation System
PubMed: 35671825
DOI: 10.1016/j.jbc.2022.102107 -
The Biochemical Journal Feb 2022Insulin rapidly stimulates GLUT4 translocation and glucose transport in fat and muscle cells. Signals from the occupied insulin receptor are translated into downstream...
Insulin rapidly stimulates GLUT4 translocation and glucose transport in fat and muscle cells. Signals from the occupied insulin receptor are translated into downstream signalling changes in serine/threonine kinases within timescales of seconds, and this is followed by delivery and accumulation of the glucose transporter GLUT4 at the plasma membrane. Kinetic studies have led to realisation that there are distinct phases of this stimulation by insulin. There is a rapid initial burst of GLUT4 delivered to the cell surface from a subcellular reservoir compartment and this is followed by a steady-state level of continuing stimulation in which GLUT4 recycles through a large itinerary of subcellular locations. Here, we provide an overview of the phases of insulin stimulation of GLUT4 translocation and the molecules that are currently considered to activate these trafficking steps. Furthermore, we suggest how use of new experimental approaches together with phospho-proteomic data may help to further identify mechanisms for activation of these trafficking processes.
Topics: Adipocytes; Animals; Cell Membrane; Glucose; Glucose Transporter Type 4; Humans; Insulin; Models, Biological; Muscle Cells; Phosphorylation; Protein Processing, Post-Translational; Protein Transport; Signal Transduction; Subcellular Fractions
PubMed: 35147164
DOI: 10.1042/BCJ20210073 -
Molecular and Cellular Biology 2023The highly conserved retromer complex controls the fate of hundreds of receptors that pass through the endolysosomal system and is a central regulatory node for diverse... (Review)
Review
The highly conserved retromer complex controls the fate of hundreds of receptors that pass through the endolysosomal system and is a central regulatory node for diverse metabolic programs. More than 20 years ago, retromer was discovered as an essential regulator of endosome-to-Golgi transport in yeast; since then, significant progress has been made to characterize how metazoan retromer components assemble to enable its engagement with endosomal membranes, where it sorts cargo receptors from endosomes to the -Golgi network or plasma membrane through recognition of sorting motifs in their cytoplasmic tails. In this review, we examine retromer regulation by exploring its assembled structure with an emphasis on how a range of adaptor proteins shape the process of receptor trafficking. Specifically, we focus on how retromer is recruited to endosomes, selects cargoes, and generates tubulovesicular carriers that deliver cargoes to target membranes. We also examine how cells adapt to distinct metabolic states by coordinating retromer expression and function. We contrast similarities and differences between retromer and its related complexes: retriever and commander/CCC, as well as their interplay in receptor trafficking. We elucidate how loss of retromer regulation is central to the pathology of various neurogenerative and metabolic diseases, as well as microbial infections, and highlight both opportunities and cautions for therapeutics that target retromer. Finally, with a focus on understanding the mechanisms that govern retromer regulation, we outline new directions for the field moving forward.
Topics: Animals; Golgi Apparatus; trans-Golgi Network; Protein Transport; Cell Membrane; Endosomes; Saccharomyces cerevisiae
PubMed: 37350516
DOI: 10.1080/10985549.2023.2222053 -
Annual Review of Plant Biology May 2023Chloroplasts are the defining plant organelles with responsibility for photosynthesis and other vital functions. To deliver these functions, they possess a complex... (Review)
Review
Chloroplasts are the defining plant organelles with responsibility for photosynthesis and other vital functions. To deliver these functions, they possess a complex proteome comprising thousands of largely nucleus-encoded proteins. Composition of the proteome is controlled by diverse processes affecting protein translocation and degradation-our focus here. Most chloroplast proteins are imported from the cytosol via multiprotein translocons in the outer and inner envelope membranes (the TOC and TIC complexes, respectively), or via one of several noncanonical pathways, and then sorted by different systems to organellar subcompartments. Chloroplast proteolysis is equally complex, involving the concerted action of internal proteases of prokaryotic origin and the nucleocytosolic ubiquitin-proteasome system (UPS). The UPS degrades unimported proteins in the cytosol and chloroplast-resident proteins via chloroplast-associated protein degradation (CHLORAD). The latter targets the TOC apparatus to regulate protein import, as well as numerous internal proteins directly, to reconfigure chloroplast functions in response to developmental and environmental signals.
Topics: Proteolysis; Proteome; Proteostasis; Chloroplasts; Ubiquitination; Chloroplast Proteins; Proteasome Endopeptidase Complex; Ubiquitin; Protein Transport; Plant Proteins
PubMed: 36854475
DOI: 10.1146/annurev-arplant-070122-032532 -
Open Biology May 2020In eukaryotic cells, about one-third of the synthesized proteins are translocated into the endoplasmic reticulum; they are membrane or lumen resident proteins and... (Review)
Review
In eukaryotic cells, about one-third of the synthesized proteins are translocated into the endoplasmic reticulum; they are membrane or lumen resident proteins and proteins direct to the Golgi apparatus. The co-translational translocation takes place through the heterotrimeric protein-conducting channel Sec61 which is associated with the ribosome and many accessory components, such as the heterotetrameric translocon-associated protein (TRAP) complex. Recently, microscopic techniques, such as cryo-electron microscopy and cryo-electron tomography, have enabled the determination of the translocation machinery structure. However, at present, there is a lack of understanding regarding the roles of some of its components; indeed, the TRAP complex function during co-translational translocation needs to be established. In addition, TRAP may play a role during unfolded protein response, endoplasmic-reticulum-associated protein degradation and congenital disorder of glycosylation (ssr4 CDG). In this article, I describe the current understanding of the TRAP complex in the light of its possible function(s).
Topics: Animals; Calcium-Binding Proteins; Cryoelectron Microscopy; Endoplasmic Reticulum; Golgi Apparatus; Humans; Membrane Glycoproteins; Models, Molecular; Protein Transport; Proteolysis; Receptors, Cytoplasmic and Nuclear; Receptors, Peptide; Unfolded Protein Response
PubMed: 32453970
DOI: 10.1098/rsob.190244 -
Cells Jan 2022The quality and quantity of membrane proteins are precisely and dynamically maintained through an endosomal recycling process. This endosomal recycling is executed by... (Review)
Review
The quality and quantity of membrane proteins are precisely and dynamically maintained through an endosomal recycling process. This endosomal recycling is executed by two protein complexes: retromer and recently identified retriever. Defects in the function of retromer or retriever cause dysregulation of many membrane proteins and result in several human disorders, including neurodegenerative disorders such as Alzheimer's disease and Parkinson's disease. Recently, neurodevelopmental disorders caused by pathogenic variants in genes associated with retriever were identified. This review focuses on the two recycling complexes and discuss their biological and developmental roles and the consequences of defects in endosomal recycling, especially in the nervous system. We also discuss future perspectives of a possible relationship of the dysfunction of retromer and retriever with neurodevelopmental disorders.
Topics: Animals; Disease Models, Animal; Endosomes; Humans; Mice; Neurodevelopmental Disorders; Protein Transport
PubMed: 35011709
DOI: 10.3390/cells11010148 -
EBioMedicine Mar 2023Vacuolar protein sorting-associated protein 35 (VPS35) is a core component of the retromer complex which mediates intracellular protein transport. It is well known that...
BACKGROUND
Vacuolar protein sorting-associated protein 35 (VPS35) is a core component of the retromer complex which mediates intracellular protein transport. It is well known that dysfunctional VPS35 functions in the accumulation of pathogenic proteins. In our previous study, VPS35 was found to be a potential gene related to poor prognosis in gastric cancer. However, the biological functions of VPS35 in gastric cancer remain unclear.
METHODS
Cell viability assays were performed to examine whether VPS35 affected cell proliferation. Immunoprecipitation and biotin assays showed that VPS35 bound to epidermal growth factor receptor (EGFR) in the cytoplasm and recycled it to the cell surface. Patient-derived xenografts and organoids were used to evaluate the effect of VPS35 on the response of gastric cancer to EGFR inhibitors.
FINDINGS
VPS35 expression levels were upregulated in tumour tissues and correlated with local tumour invasion and poor survival in patients with gastric cancer. VPS35 promoted cell proliferation and increased tumour growth. Mechanistically, VPS35 selectively bound to endocytosed EGFR in early endosomes and recycled it back to the cell surface, leading to the downstream activation of the ERK1/2 pathway. We also found that high VPS35 expression levels increased the sensitivity of the xenograft and organoid models to EGFR inhibitors.
INTERPRETATION
VPS35 promotes cell proliferation by recycling EGFR to the cell surface, amplifying the network of receptor trafficking. VPS35 expression levels are positively correlated with gastric cancer sensitivity to EGFR inhibitors, which offers a potential method to stratify patients for EGFR inhibitor utilisation.
FUNDING
National Natural Science Foundation of China.
Topics: Humans; Carrier Proteins; Cell Proliferation; ErbB Receptors; Protein Transport; Stomach Neoplasms; Vesicular Transport Proteins
PubMed: 36738481
DOI: 10.1016/j.ebiom.2023.104451 -
Molecules (Basel, Switzerland) Apr 2023Protein glycosylation is a general post-translational modification pathway that controls various biological functions including protein trafficking, cell adhesion, and...
Protein glycosylation is a general post-translational modification pathway that controls various biological functions including protein trafficking, cell adhesion, and protein-ligand interaction [...].
Topics: Glycosylation; Protein Processing, Post-Translational; Protein Transport; Cell Adhesion
PubMed: 37050026
DOI: 10.3390/molecules28073263 -
Cells Sep 2019Efficiency and fidelity of protein secretion are achieved thanks to the presence of different steps, located sequentially in time and space along the secretory... (Review)
Review
Efficiency and fidelity of protein secretion are achieved thanks to the presence of different steps, located sequentially in time and space along the secretory compartment, controlling protein folding and maturation. After entering into the endoplasmic reticulum (ER), secretory proteins attain their native structure thanks to specific chaperones and enzymes. Only correctly folded molecules are allowed by quality control (QC) mechanisms to leave the ER and proceed to downstream compartments. Proteins that cannot fold properly are instead retained in the ER to be finally destined to proteasomal degradation. Exiting from the ER requires, in most cases, the use of coated vesicles, departing at the ER exit sites, which will fuse with the Golgi compartment, thus releasing their cargoes. Protein accumulation in the ER can be caused by a too stringent QC or by ineffective transport: these situations could be deleterious for the organism, due to the loss of the secreted protein, and to the cell itself, because of abnormal increase of protein concentration in the ER. In both cases, diseases can arise. In this review, we will describe the pathophysiology of protein folding and transport between the ER and the Golgi compartment.
Topics: Biological Transport; COP-Coated Vesicles; Endoplasmic Reticulum; Golgi Apparatus; Protein Folding; Protein Transport; Proteins
PubMed: 31500301
DOI: 10.3390/cells8091051