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Seminars in Cell & Developmental Biology Nov 2018Eukaryotic cells have a highly evolved system of protein secretion, and dysfunction in this pathway is associated with many diseases including cancer, infection,... (Review)
Review
Eukaryotic cells have a highly evolved system of protein secretion, and dysfunction in this pathway is associated with many diseases including cancer, infection, metabolic disease and neurological disorders. Most proteins are secreted using the conventional endoplasmic reticulum (ER)/Golgi network and as such, this pathway is well-characterised. However, several cytosolic proteins have now been documented as secreted by unconventional transport pathways. This review focuses on two of these proteins families: annexins and galectins. The extracellular functions of these proteins are well documented, as are associations of their perturbed secretion with several diseases. However, the mechanisms and regulation of their secretion remain poorly characterised, and are discussed in this review. This review is part of a Special Issues of SCDB on 'unconventional protein secretion' edited by Walter Nickel and Catherine Rabouille.
Topics: Annexins; Galectins; Humans; Protein Transport
PubMed: 29501720
DOI: 10.1016/j.semcdb.2018.02.022 -
Current Opinion in Cell Biology Apr 2022In eukaryotes, there is now compelling evidence that in addition to the conventional endoplasmic reticulum-Golgi secretory pathway, there are additional routes for the... (Review)
Review
In eukaryotes, there is now compelling evidence that in addition to the conventional endoplasmic reticulum-Golgi secretory pathway, there are additional routes for the export of cytoplasmic proteins with a critical role in numerous physio-pathological conditions. These alternative secretory pathways or unconventional protein secretion (UPS) start now to be molecularly dissected, and while UPS landscape appears to be governed by a striking diversity and heterogeneity of mechanisms, common principles are emerging. We review here the role of key molecular determinants as well as the role of central hubs for UPS, highlighting the plasticity and dynamic properties of membrane-bound compartments. We also describe recent findings that position UPS as an integral component of adaptive responses to cope with particular cellular needs and stresses.
Topics: Endoplasmic Reticulum; Golgi Apparatus; Protein Transport; Proteins; Secretory Pathway
PubMed: 35305454
DOI: 10.1016/j.ceb.2022.02.006 -
Molecular Cell Aug 2018The billions of proteins inside a eukaryotic cell are organized among dozens of sub-cellular compartments, within which they are further organized into protein... (Review)
Review
The billions of proteins inside a eukaryotic cell are organized among dozens of sub-cellular compartments, within which they are further organized into protein complexes. The maintenance of both levels of organization is crucial for normal cellular function. Newly made proteins that fail to be segregated to the correct compartment or assembled into the appropriate complex are defined as orphans. In this review, we discuss the challenges faced by a cell of minimizing orphaned proteins, the quality control systems that recognize orphans, and the consequences of excess orphans for protein homeostasis and disease.
Topics: Protein Biosynthesis; Protein Transport; Proteins; Proteolysis; Proteostasis
PubMed: 30075143
DOI: 10.1016/j.molcel.2018.07.001 -
Physiological Reviews Jan 2017Newly synthesized transmembrane proteins undergo a series of steps to ensure that only the required amount of correctly folded protein is localized to the membrane. The... (Review)
Review
Newly synthesized transmembrane proteins undergo a series of steps to ensure that only the required amount of correctly folded protein is localized to the membrane. The regulation of protein quality and its abundance at the membrane are often controlled by ubiquitination, a multistep enzymatic process that results in the attachment of ubiquitin, or chains of ubiquitin to the target protein. Protein ubiquitination acts as a signal for sorting, trafficking, and the removal of membrane proteins via endocytosis, a process through which multiple ubiquitin ligases are known to specifically regulate the functions of a number of ion channels, transporters, and signaling receptors. Endocytic removal of these proteins through ubiquitin-dependent endocytosis provides a way to rapidly downregulate the physiological outcomes, and defects in such controls are directly linked to human pathologies. Recent evidence suggests that ubiquitination is also involved in the shedding of membranes and associated proteins as extracellular vesicles, thereby not only controlling the cell surface levels of some membrane proteins, but also their potential transport to neighboring cells. In this review, we summarize the mechanisms and functions of ubiquitination of membrane proteins and provide specific examples of ubiquitin-dependent regulation of membrane proteins.
Topics: Animals; Humans; Membrane Proteins; Protein Transport; Ubiquitination
PubMed: 27932395
DOI: 10.1152/physrev.00012.2016 -
Developmental Biology Sep 2022Neurons are highly polarized cells with extensive axonal and dendritic projections that send and receive signals over long distances. Neuronal polarity requires sorting... (Review)
Review
Neurons are highly polarized cells with extensive axonal and dendritic projections that send and receive signals over long distances. Neuronal polarity requires sorting and maintaining a unique set of proteins to the neuron's distinct axonal and somatodendritic domains. The axon initial segment (AIS) is a specialized subcellular region located between these two domains and is critical for neuronal polarity. The AIS has a complex and elaborately organized molecular structure that enables its functions in neuronal polarity. Disruption of the AIS is associated with neurodevelopmental and neuropsychiatric disease pathologies, thus highlighting the importance of the AIS in neuronal physiology. This review discusses recent progress toward understanding the molecular architecture of the AIS and its importance in neuronal polarity through regulating protein diffusion and vesicular trafficking.
Topics: Axon Initial Segment; Axons; Cell Polarity; Neurons; Protein Transport
PubMed: 35640681
DOI: 10.1016/j.ydbio.2022.05.016 -
Cellular Microbiology Jul 2020The ability of eukaryotic parasites from the phylum Apicomplexa to cause devastating diseases is predicated upon their ability to maintain faithful and precise protein... (Review)
Review
The ability of eukaryotic parasites from the phylum Apicomplexa to cause devastating diseases is predicated upon their ability to maintain faithful and precise protein trafficking mechanisms. Their parasitic life cycle depends on the trafficking of effector proteins to the infected host cell, transport of proteins to several critical organelles required for survival, as well as transport of parasite and host proteins to the digestive organelles to generate the building blocks for parasite growth. Several recent studies have shed light on the molecular mechanisms parasites utilise to transform the infected host cells, transport proteins to essential metabolic organelles and for biogenesis of organelles required for continuation of their life cycle. Here, we review key pathways of protein transport originating and branching from the endoplasmic reticulum, focusing on the essential roles of chaperones in these processes. Further, we highlight key gaps in our knowledge that prevents us from building a holistic view of protein trafficking in these deadly human pathogens.
Topics: Animals; Apicomplexa; Apicoplasts; Endoplasmic Reticulum; Humans; Malaria; Parasites; Protein Transport; Protozoan Proteins; Vacuoles
PubMed: 32388921
DOI: 10.1111/cmi.13215 -
Biochimica Et Biophysica Acta.... Jan 2021Outer membrane proteins integrate mitochondria into the cellular environment. They warrant exchange of small molecules like metabolites and ions, transport proteins into... (Review)
Review
Outer membrane proteins integrate mitochondria into the cellular environment. They warrant exchange of small molecules like metabolites and ions, transport proteins into mitochondria, form contact sites to other cellular organelles for lipid exchange, constitute a signaling platform for apoptosis and inflammation and mediate organelle fusion and fission. The outer membrane contains two types of integral membrane proteins. Proteins with a transmembrane β-barrel structure and proteins with a single or multiple α-helical membrane spans. All outer membrane proteins are produced on cytosolic ribosomes and imported into the target organelle. Precursors of β-barrel and α-helical proteins are transported into the outer membrane via distinct import routes. The translocase of the outer membrane (TOM complex) transports β-barrel precursors across the outer membrane and the sorting and assembly machinery (SAM complex) inserts them into the target membrane. The mitochondrial import (MIM) complex constitutes the major integration site for α-helical embedded proteins. The import of some MIM-substrates involves TOM receptors, while others are imported in a TOM-independent manner. Remarkably, TOM, SAM and MIM complexes dynamically interact to import a large set of different proteins and to coordinate their assembly into protein complexes. Thus, protein import into the mitochondrial outer membrane involves a dynamic platform of protein translocases.
Topics: Animals; Humans; Membrane Transport Proteins; Mitochondria; Mitochondrial Membranes; Mitochondrial Proteins; Protein Transport
PubMed: 33035511
DOI: 10.1016/j.bbabio.2020.148323 -
Bioscience Reports Aug 2011Segregation of the apical and basolateral plasma membrane domains is the key distinguishing feature of epithelial cells. A series of interrelated cues and processes... (Review)
Review
Segregation of the apical and basolateral plasma membrane domains is the key distinguishing feature of epithelial cells. A series of interrelated cues and processes follow this primary polarization event, resulting in the morphogenesis of the mammalian epithelium. This review focuses on the role of the interactions between the extracellular matrix and neighbouring cells during the initiation and establishment of epithelial polarity, and the role that membrane transport and polarity complexes play in this process. An overview of the formation of the apical junctional complexes is given in relation to the generation of distinct membrane domains characterized by the asymmetric distribution of phosphoinositides and proteins. The mechanisms and machinery utilized by the trafficking pathways involved in the generation and maintenance of this apical-basolateral polarization are expounded, highlighting processes of apical-directed transport. Furthermore, the current proposed mechanisms for the organization of entire networks of cells into a structured, polarized three-dimensional structure are described, with an emphasis on the proposed mechanisms for the formation and expansion of the apical lumen.
Topics: Animals; Cell Membrane; Cell Polarity; Endocytosis; Epithelial Cells; Humans; Morphogenesis; Protein Transport; Signal Transduction
PubMed: 21366541
DOI: 10.1042/BSR20100119 -
Genetics Research Dec 2019Regulated transport through the secretory pathway is essential for embryonic development and homeostasis. Disruptions in this process impact cell fate, differentiation... (Review)
Review
Regulated transport through the secretory pathway is essential for embryonic development and homeostasis. Disruptions in this process impact cell fate, differentiation and survival, often resulting in abnormalities in morphogenesis and in disease. Several congenital malformations are caused by mutations in genes coding for proteins that regulate cargo protein transport in the secretory pathway. The severity of mutant phenotypes and the unclear aetiology of transport protein-associated pathologies have motivated research on the regulation and mechanisms through which these proteins contribute to morphogenesis. This review focuses on the role of the p24/transmembrane emp24 domain (TMED) family of cargo receptors in development and disease.
Topics: Animals; Carrier Proteins; Humans; Intracellular Membranes; Membrane Proteins; Protein Transport; Transport Vesicles; Vesicular Transport Proteins
PubMed: 31878985
DOI: 10.1017/S0016672319000090 -
Genes To Cells : Devoted To Molecular &... Jul 2012The nuclear-cytoplasmic protein transport is a critical process in cellular events. The identification of transport signals (nuclear localization signal and nuclear... (Review)
Review
The nuclear-cytoplasmic protein transport is a critical process in cellular events. The identification of transport signals (nuclear localization signal and nuclear export signal) and their receptors has facilitated our understanding of this expanding field. Nuclear transport must be appropriately regulated to deliver proteins through the nuclear pore when their functions are required in the nucleus, and to export them into the cytoplasm when they are not needed in the nucleus. Altered nuclear transport processes have been observed in stressed cells, which would change gene expressions. Some viruses interfere with nuclear transport in host cells to evade immune defense. Moreover, certain transport factors negatively regulate nuclear protein transport in cells. Understanding the regulatory mechanisms of nuclear-cytoplasmic trafficking not only provides important information about cellular processes, but also is of use for developing specific inhibitors for transport pathways.
Topics: Active Transport, Cell Nucleus; Carrier Proteins; Cell Nucleus; Humans; Nuclear Localization Signals; Nuclear Proteins; Peptides; Protein Binding; Protein Processing, Post-Translational; Protein Transport; Stress, Physiological; Viral Proteins
PubMed: 22672474
DOI: 10.1111/j.1365-2443.2012.01609.x