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16 pages, 3171 KiB

Open AccessArticle

Cdc42 Couples T Cell Receptor Endocytosis to GRAF1-Mediated Tubular Invaginations of the Plasma Membrane

by Pascal Rossatti, Luca Ziegler, Richard Schregle, Verena M. Betzler, Manuela Ecker and Jérémie Rossy

Cells 2019, 8(11), 1388; https://doi.org/10.3390/cells8111388 - 04 Nov 2019

Cited by 12 | Viewed by 4613

Abstract

T cell activation is immediately followed by internalization of the T cell receptor (TCR). TCR endocytosis is required for T cell activation, but the mechanisms supporting removal of TCR from the cell surface remain incompletely understood. Here we report that TCR endocytosis is [...] Read more.

T cell activation is immediately followed by internalization of the T cell receptor (TCR). TCR endocytosis is required for T cell activation, but the mechanisms supporting removal of TCR from the cell surface remain incompletely understood. Here we report that TCR endocytosis is linked to the clathrin-independent carrier (CLIC) and GPI-enriched endocytic compartments (GEEC) endocytic pathway. We show that unlike the canonical clathrin cargo transferrin or the adaptor protein Lat, internalized TCR accumulates in tubules shaped by the small GTPase Cdc42 and the Bin/amphiphysin/Rvs (BAR) domain containing protein GRAF1 in T cells. Preventing GRAF1-positive tubules to mature into endocytic vesicles by expressing a constitutively active Cdc42 impairs the endocytosis of TCR, while having no consequence on the uptake of transferrin. Together, our data reveal a link between TCR internalization and the CLIC/GEEC endocytic route supported by Cdc42 and GRAF1. Full article

(This article belongs to the Special Issue Membrane Traffic in Health and Disease)

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Review

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11 pages, 294 KiB

Open AccessFeature PaperReview

ER-to-Golgi Trafficking and Its Implication in Neurological Diseases

by Bo Wang, Katherine R. Stanford and Mondira Kundu

Cells 2020, 9(2), 408; https://doi.org/10.3390/cells9020408 - 11 Feb 2020

Cited by 30 | Viewed by 4710

Abstract

Membrane and secretory proteins are essential for almost every aspect of cellular function. These proteins are incorporated into ER-derived carriers and transported to the Golgi before being sorted for delivery to their final destination. Although ER-to-Golgi trafficking is highly conserved among eukaryotes, several [...] Read more.

Membrane and secretory proteins are essential for almost every aspect of cellular function. These proteins are incorporated into ER-derived carriers and transported to the Golgi before being sorted for delivery to their final destination. Although ER-to-Golgi trafficking is highly conserved among eukaryotes, several layers of complexity have been added to meet the increased demands of complex cell types in metazoans. The specialized morphology of neurons and the necessity for precise spatiotemporal control over membrane and secretory protein localization and function make them particularly vulnerable to defects in trafficking. This review summarizes the general mechanisms involved in ER-to-Golgi trafficking and highlights mutations in genes affecting this process, which are associated with neurological diseases in humans. Full article

(This article belongs to the Special Issue Membrane Traffic in Health and Disease)

23 pages, 1019 KiB

Open AccessReview

Spatiotemporal Control of Intracellular Membrane Trafficking by Rho GTPases

by Monilola A. Olayioye, Bettina Noll and Angelika Hausser

Cells 2019, 8(12), 1478; https://doi.org/10.3390/cells8121478 - 21 Nov 2019

Cited by 21 | Viewed by 6498

Abstract

As membrane-associated master regulators of cytoskeletal remodeling, Rho GTPases coordinate a wide range of biological processes such as cell adhesion, motility, and polarity. In the last years, Rho GTPases have also been recognized to control intracellular membrane sorting and trafficking steps directly; however, [...] Read more.

As membrane-associated master regulators of cytoskeletal remodeling, Rho GTPases coordinate a wide range of biological processes such as cell adhesion, motility, and polarity. In the last years, Rho GTPases have also been recognized to control intracellular membrane sorting and trafficking steps directly; however, how Rho GTPase signaling is regulated at endomembranes is still poorly understood. In this review, we will specifically address the local Rho GTPase pools coordinating intracellular membrane trafficking with a focus on the endo- and exocytic pathways. We will further highlight the spatiotemporal molecular regulation of Rho signaling at endomembrane sites through Rho regulatory proteins, the GEFs and GAPs. Finally, we will discuss the contribution of dysregulated Rho signaling emanating from endomembranes to the development and progression of cancer. Full article

(This article belongs to the Special Issue Membrane Traffic in Health and Disease)

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22 pages, 2112 KiB

Open AccessFeature PaperEditor’s ChoiceReview

Control of Protein Homeostasis in the Early Secretory Pathway: Current Status and Challenges

by Daria Sicari, Aeid Igbaria and Eric Chevet

Cells 2019, 8(11), 1347; https://doi.org/10.3390/cells8111347 - 29 Oct 2019

Cited by 29 | Viewed by 8717

Abstract

Discrimination between properly folded proteins and those that do not reach this state is necessary for cells to achieve functionality. Eukaryotic cells have evolved several mechanisms to ensure secretory protein quality control, which allows efficiency and fidelity in protein production. Among the actors [...] Read more.

Discrimination between properly folded proteins and those that do not reach this state is necessary for cells to achieve functionality. Eukaryotic cells have evolved several mechanisms to ensure secretory protein quality control, which allows efficiency and fidelity in protein production. Among the actors involved in such process, both endoplasmic reticulum (ER) and the Golgi complex play prominent roles in protein synthesis, biogenesis and secretion. ER and Golgi functions ensure that only properly folded proteins are allowed to flow through the secretory pathway while improperly folded proteins have to be eliminated to not impinge on cellular functions. Thus, complex quality control and degradation machineries are crucial to prevent the toxic accumulation of improperly folded proteins. However, in some instances, improperly folded proteins can escape the quality control systems thereby contributing to several human diseases. Herein, we summarize how the early secretory pathways copes with the accumulation of improperly folded proteins, and how insufficient handling can cause the development of several human diseases. Finally, we detail the genetic and pharmacologic approaches that could be used as potential therapeutic tools to treat these diseases. Full article

(This article belongs to the Special Issue Membrane Traffic in Health and Disease)

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52 pages, 2433 KiB

Open AccessReview

Endocytic Adaptor Proteins in Health and Disease: Lessons from Model Organisms and Human Mutations

by Domenico Azarnia Tehran, Tania López-Hernández and Tanja Maritzen

Cells 2019, 8(11), 1345; https://doi.org/10.3390/cells8111345 - 29 Oct 2019

Cited by 24 | Viewed by 5663

Abstract

Cells need to exchange material and information with their environment. This is largely achieved via cell-surface receptors which mediate processes ranging from nutrient uptake to signaling responses. Consequently, their surface levels have to be dynamically controlled. Endocytosis constitutes a powerful mechanism to regulate [...] Read more.

Cells need to exchange material and information with their environment. This is largely achieved via cell-surface receptors which mediate processes ranging from nutrient uptake to signaling responses. Consequently, their surface levels have to be dynamically controlled. Endocytosis constitutes a powerful mechanism to regulate the surface proteome and to recycle vesicular transmembrane proteins that strand at the plasma membrane after exocytosis. For efficient internalization, the cargo proteins need to be linked to the endocytic machinery via adaptor proteins such as the heterotetrameric endocytic adaptor complex AP-2 and a variety of mostly monomeric endocytic adaptors. In line with the importance of endocytosis for nutrient uptake, cell signaling and neurotransmission, animal models and human mutations have revealed that defects in these adaptors are associated with several diseases ranging from metabolic disorders to encephalopathies. This review will discuss the physiological functions of the so far known adaptor proteins and will provide a comprehensive overview of their links to human diseases. Full article

(This article belongs to the Special Issue Membrane Traffic in Health and Disease)

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18 pages, 1834 KiB

Open AccessReview

Activity and Trafficking of Copper-Transporting ATPases in Tumor Development and Defense against Platinum-Based Drugs

by Raffaella Petruzzelli and Roman S. Polishchuk

Cells 2019, 8(9), 1080; https://doi.org/10.3390/cells8091080 - 13 Sep 2019

Cited by 56 | Viewed by 4494

Abstract

Membrane trafficking pathways emanating from the Golgi regulate a wide range of cellular processes. One of these is the maintenance of copper (Cu) homeostasis operated by the Golgi-localized Cu-transporting ATPases ATP7A and ATP7B. At the Golgi, these proteins supply Cu to newly synthesized [...] Read more.

Membrane trafficking pathways emanating from the Golgi regulate a wide range of cellular processes. One of these is the maintenance of copper (Cu) homeostasis operated by the Golgi-localized Cu-transporting ATPases ATP7A and ATP7B. At the Golgi, these proteins supply Cu to newly synthesized enzymes which use this metal as a cofactor to catalyze a number of vitally important biochemical reactions. However, in response to elevated Cu, the Golgi exports ATP7A/B to post-Golgi sites where they promote sequestration and efflux of excess Cu to limit its potential toxicity. Growing tumors actively consume Cu and employ ATP7A/B to regulate the availability of this metal for oncogenic enzymes such as LOX and LOX-like proteins, which confer higher invasiveness to malignant cells. Furthermore, ATP7A/B activity and trafficking allow tumor cells to detoxify platinum (Pt)-based drugs (like cisplatin), which are used for the chemotherapy of different solid tumors. Despite these noted activities of ATP7A/B that favor oncogenic processes, the mechanisms that regulate the expression and trafficking of Cu ATPases in malignant cells are far from being completely understood. This review summarizes current data on the role of ATP7A/B in the regulation of Cu and Pt metabolism in malignant cells and outlines questions and challenges that should be addressed to understand how ATP7A and ATP7B trafficking mechanisms might be targeted to counteract tumor development. Full article

(This article belongs to the Special Issue Membrane Traffic in Health and Disease)

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16 pages, 866 KiB

Open AccessFeature PaperReview

How to Avoid a No-Deal ER Exit

by Tiziana Anelli and Paola Panina-Bordignon

Cells 2019, 8(9), 1051; https://doi.org/10.3390/cells8091051 - 07 Sep 2019

Cited by 5 | Viewed by 5744

Abstract

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 [...] Read more.

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. Full article

(This article belongs to the Special Issue Membrane Traffic in Health and Disease)

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20 pages, 1572 KiB

Open AccessEditor’s ChoiceReview

Membrane-Bound Meet Membraneless in Health and Disease

by Chujun Zhang and Catherine Rabouille

Cells 2019, 8(9), 1000; https://doi.org/10.3390/cells8091000 - 29 Aug 2019

Cited by 16 | Viewed by 5372

Abstract

Membraneless organelles (MLOs) are defined as cellular structures that are not sealed by a lipidic membrane and are shown to form by phase separation. They exist in both the nucleus and the cytoplasm that is also heavily populated by numerous membrane-bound organelles. Even [...] Read more.

Membraneless organelles (MLOs) are defined as cellular structures that are not sealed by a lipidic membrane and are shown to form by phase separation. They exist in both the nucleus and the cytoplasm that is also heavily populated by numerous membrane-bound organelles. Even though the name membraneless suggests that MLOs are free of membrane, both membrane and factors regulating membrane trafficking steps are emerging as important components of MLO formation and function. As a result, we name them biocondensates. In this review, we examine the relationships between biocondensates and membrane. First, inhibition of membrane trafficking in the early secretory pathway leads to the formation of biocondensates (P-bodies and Sec bodies). In the same vein, stress granules have a complex relationship with the cyto-nuclear transport machinery. Second, membrane contributes to the regulated formation of phase separation in the cells and we will present examples including clustering at the plasma membrane and at the synapse. Finally, the whole cell appears to transit from an interphase phase-separated state to a mitotic diffuse state in a DYRK3 dependent manner. This firmly establishes a crosstalk between the two types of cell organization that will need to be further explored. Full article

(This article belongs to the Special Issue Membrane Traffic in Health and Disease)

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33 pages, 1125 KiB

Open AccessFeature PaperReview

Mechanisms and Pathophysiological Roles of the ATG8 Conjugation Machinery

by Alf Håkon Lystad and Anne Simonsen

Cells 2019, 8(9), 973; https://doi.org/10.3390/cells8090973 - 25 Aug 2019

Cited by 50 | Viewed by 8171

Abstract

Since their initial discovery around two decades ago, the yeast autophagy-related (Atg)8 protein and its mammalian homologues of the light chain 3 (LC3) and γ-aminobutyric acid receptor associated proteins (GABARAP) families have been key for the tremendous expansion of our knowledge about autophagy, [...] Read more.

Since their initial discovery around two decades ago, the yeast autophagy-related (Atg)8 protein and its mammalian homologues of the light chain 3 (LC3) and γ-aminobutyric acid receptor associated proteins (GABARAP) families have been key for the tremendous expansion of our knowledge about autophagy, a process in which cytoplasmic material become targeted for lysosomal degradation. These proteins are ubiquitin-like proteins that become directly conjugated to a lipid in the autophagy membrane upon induction of autophagy, thus providing a marker of the pathway, allowing studies of autophagosome biogenesis and maturation. Moreover, the ATG8 proteins function to recruit components of the core autophagy machinery as well as cargo for selective degradation. Importantly, comprehensive structural and biochemical in vitro studies of the machinery required for ATG8 protein lipidation, as well as their genetic manipulation in various model organisms, have provided novel insight into the molecular mechanisms and pathophysiological roles of the mATG8 proteins. Recently, it has become evident that the ATG8 proteins and their conjugation machinery are also involved in intracellular pathways and processes not related to autophagy. This review focuses on the molecular functions of ATG8 proteins and their conjugation machinery in autophagy and other pathways, as well as their links to disease. Full article

(This article belongs to the Special Issue Membrane Traffic in Health and Disease)

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17 pages, 1660 KiB

Open AccessFeature PaperReview

The NAE Pathway: Autobahn to the Nucleus for Cell Surface Receptors

by Poonam Shah, Alexandre Chaumet, Stephen J. Royle and Frederic A. Bard

Cells 2019, 8(8), 915; https://doi.org/10.3390/cells8080915 - 16 Aug 2019

Cited by 22 | Viewed by 6846

Abstract

Various growth factors and full-length cell surface receptors such as EGFR are translocated from the cell surface to the nucleoplasm, baffling cell biologists to the mechanisms and functions of this process. Elevated levels of nuclear EGFR correlate with poor prognosis in various cancers. [...] Read more.

Various growth factors and full-length cell surface receptors such as EGFR are translocated from the cell surface to the nucleoplasm, baffling cell biologists to the mechanisms and functions of this process. Elevated levels of nuclear EGFR correlate with poor prognosis in various cancers. In recent years, nuclear EGFR has been implicated in regulating gene transcription, cell proliferation and DNA damage repair. Different models have been proposed to explain how the receptors are transported into the nucleus. However, a clear consensus has yet to be reached. Recently, we described the nuclear envelope associated endosomes (NAE) pathway, which delivers EGFR from the cell surface to the nucleus. This pathway involves transport, docking and fusion of NAEs with the outer membrane of the nuclear envelope. EGFR is then presumed to be transported through the nuclear pore complex, extracted from membranes and solubilised. The SUN1/2 nuclear envelope proteins, Importin-beta, nuclear pore complex proteins and the Sec61 translocon have been implicated in the process. While this framework can explain the cell surface to nucleus traffic of EGFR and other cell surface receptors, it raises several questions that we consider in this review, together with implications for health and disease. Full article

(This article belongs to the Special Issue Membrane Traffic in Health and Disease)

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25 pages, 1209 KiB

Open AccessReview

Rab GTPases: Switching to Human Diseases

by Noemi Antonella Guadagno and Cinzia Progida

Cells 2019, 8(8), 909; https://doi.org/10.3390/cells8080909 - 16 Aug 2019

Cited by 54 | Viewed by 9163

Abstract

Rab proteins compose the largest family of small GTPases and control the different steps of intracellular membrane traffic. More recently, they have been shown to also regulate cell signaling, division, survival, and migration. The regulation of these processes generally occurs through recruitment of [...] Read more.

Rab proteins compose the largest family of small GTPases and control the different steps of intracellular membrane traffic. More recently, they have been shown to also regulate cell signaling, division, survival, and migration. The regulation of these processes generally occurs through recruitment of effectors and regulatory proteins, which control the association of Rab proteins to membranes and their activation state. Alterations in Rab proteins and their effectors are associated with multiple human diseases, including neurodegeneration, cancer, and infections. This review provides an overview of how the dysregulation of Rab-mediated functions and membrane trafficking contributes to these disorders. Understanding the altered dynamics of Rabs and intracellular transport defects might thus shed new light on potential therapeutic strategies. Full article

(This article belongs to the Special Issue Membrane Traffic in Health and Disease)

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19 pages, 310 KiB

Open AccessReview

Golgi Fragmentation in Neurodegenerative Diseases: Is There a Common Cause?

by José Ángel Martínez-Menárguez, Mónica Tomás, Narcisa Martínez-Martínez and Emma Martínez-Alonso

Cells 2019, 8(7), 748; https://doi.org/10.3390/cells8070748 - 19 Jul 2019

Cited by 44 | Viewed by 6911

Abstract

In most mammalian cells, the Golgi complex forms a continuous ribbon. In neurodegenerative diseases, the Golgi ribbon of a specific group of neurons is typically broken into isolated elements, a very early event which happens before clinical and other pathological symptoms become evident. [...] Read more.

In most mammalian cells, the Golgi complex forms a continuous ribbon. In neurodegenerative diseases, the Golgi ribbon of a specific group of neurons is typically broken into isolated elements, a very early event which happens before clinical and other pathological symptoms become evident. It is not known whether this phenomenon is caused by mechanisms associated with cell death or if, conversely, it triggers apoptosis. When the phenomenon was studied in diseases such as Parkinson’s and Alzheimer’s or amyotrophic lateral sclerosis, it was attributed to a variety of causes, including the presence of cytoplasmatic protein aggregates, malfunctioning of intracellular traffic and/or alterations in the cytoskeleton. In the present review, we summarize the current findings related to these and other neurodegenerative diseases and try to search for clues on putative common causes. Full article

(This article belongs to the Special Issue Membrane Traffic in Health and Disease)

22 pages, 2819 KiB

Open AccessReview

Cargo Sorting at the trans-Golgi Network for Shunting into Specific Transport Routes: Role of Arf Small G Proteins and Adaptor Complexes

by Jing Zhi Anson Tan and Paul Anthony Gleeson

Cells 2019, 8(6), 531; https://doi.org/10.3390/cells8060531 - 03 Jun 2019

Cited by 36 | Viewed by 8077

Abstract

The trans-Golgi network (TGN) is responsible for selectively recruiting newly synthesized cargo into transport carriers for delivery to their appropriate destination. In addition, the TGN is responsible for receiving and recycling cargo from endosomes. The membrane organization of the TGN facilitates the [...] Read more.

The trans-Golgi network (TGN) is responsible for selectively recruiting newly synthesized cargo into transport carriers for delivery to their appropriate destination. In addition, the TGN is responsible for receiving and recycling cargo from endosomes. The membrane organization of the TGN facilitates the sorting of cargoes into distinct populations of transport vesicles. There have been significant advances in defining the molecular mechanism involved in the recognition of membrane cargoes for recruitment into different populations of transport carriers. This machinery includes cargo adaptors of the adaptor protein (AP) complex family, and monomeric Golgi-localized γ ear-containing Arf-binding protein (GGA) family, small G proteins, coat proteins, as well as accessory factors to promote budding and fission of transport vesicles. Here, we review this literature with a particular focus on the transport pathway(s) mediated by the individual cargo adaptors and the cargo motifs recognized by these adaptors. Defects in these cargo adaptors lead to a wide variety of diseases. Full article

(This article belongs to the Special Issue Membrane Traffic in Health and Disease)

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