-
Cellular and Molecular Life Sciences :... Apr 2016Neurodegenerative diseases are amongst the most devastating of human disorders. New technologies have led to a rapid increase in the identification of disease-related... (Review)
Review
Neurodegenerative diseases are amongst the most devastating of human disorders. New technologies have led to a rapid increase in the identification of disease-related genes with an enhanced appreciation of the key roles played by genetics in the etiology of these disorders. Importantly, pinpointing the normal function of disease gene proteins leads to new understanding of the cellular machineries and pathways that are altered in the disease process. One such emerging pathway is membrane trafficking in the endosomal system. This key cellular process controls the localization and levels of a myriad of proteins and is thus critical for normal cell function. In this review we will focus on three neurodegenerative diseases; Parkinson disease, amyotrophic lateral sclerosis, and hereditary spastic paraplegias, for which a large number of newly discovered disease genes encode proteins that function in endosomal membrane trafficking. We will describe how alterations in these proteins affect endosomal function and speculate on the contributions of these disruptions to disease pathophysiology.
Topics: Amyotrophic Lateral Sclerosis; Autophagy; Clathrin-Coated Vesicles; Endocytosis; Humans; Lysosomes; Multivesicular Bodies; Parkinson Disease; Protein Transport; Spastic Paraplegia, Hereditary
PubMed: 26721251
DOI: 10.1007/s00018-015-2105-x -
F1000Research 2018Platelet granules are unique among secretory vesicles in both their content and their life cycle. Platelets contain three major granule types-dense granules,... (Review)
Review
Platelet granules are unique among secretory vesicles in both their content and their life cycle. Platelets contain three major granule types-dense granules, α-granules, and lysosomes-although other granule types have been reported. Dense granules and α-granules are the most well-studied and the most physiologically important. Platelet granules are formed in large, multilobulated cells, termed megakaryocytes, prior to transport into platelets. The biogenesis of dense granules and α-granules involves common but also distinct pathways. Both are formed from the -Golgi network and early endosomes and mature in multivesicular bodies, but the formation of dense granules requires trafficking machinery different from that of α-granules. Following formation in the megakaryocyte body, both granule types are transported through and mature in long proplatelet extensions prior to the release of nascent platelets into the bloodstream. Granules remain stored in circulating platelets until platelet activation triggers the exocytosis of their contents. Soluble -ethylmaleimide-sensitive factor attachment protein receptor (SNARE) proteins, located on both the granules and target membranes, provide the mechanical energy that enables membrane fusion during both granulogenesis and exocytosis. The function of these core fusion engines is controlled by SNARE regulators, which direct the site, timing, and extent to which these SNAREs interact and consequently the resulting membrane fusion. In this review, we assess new developments in the study of platelet granules, from their generation to their exocytosis.
PubMed: 29560259
DOI: 10.12688/f1000research.13283.1 -
Frontiers in Genetics 2022The primary cilium is a microtubule-based organelle that extends from a basal body at the surface of most cells. This antenna is an efficient sensor of the cell... (Review)
Review
The primary cilium is a microtubule-based organelle that extends from a basal body at the surface of most cells. This antenna is an efficient sensor of the cell micro-environment and is instrumental to the proper development and homeostatic control of organs. Recent compelling studies indicate that, in addition to its role as a sensor, the primary cilium also emits signals through the release of bioactive extracellular vesicles (EVs). While some primary-cilium derived EVs are released through an actin-dependent ectocytosis and are called ectosomes (or large EVs, 350-500 nm), others originate from the exocytosis of multivesicular bodies and are smaller (small EVs, 50-100 nm). Ciliary EVs carry unique signaling factors, including protein markers and microRNAs (miRNAs), and participate in intercellular communication in different organism models. This review discusses the mechanism of release, the molecular features, and functions of EVs deriving from cilia, based on the existing literature.
PubMed: 36061180
DOI: 10.3389/fgene.2022.916233 -
Traffic (Copenhagen, Denmark) Jan 2020The late endosomes/endo-lysosomes of vertebrates contain an atypical phospholipid, lysobisphosphatidic acid (LBPA) (also termed bis[monoacylglycero]phosphate [BMP]),... (Review)
Review
The late endosomes/endo-lysosomes of vertebrates contain an atypical phospholipid, lysobisphosphatidic acid (LBPA) (also termed bis[monoacylglycero]phosphate [BMP]), which is not detected elsewhere in the cell. LBPA is abundant in the membrane system present in the lumen of this compartment, including intralumenal vesicles (ILVs). In this review, the current knowledge on LBPA and LBPA-containing membranes will be summarized, and their role in the control of endosomal cholesterol will be outlined. Some speculations will also be made on how this system may be overwhelmed in the cholesterol storage disorder Niemann-Pick C. Then, the roles of intralumenal membranes in endo-lysosomal dynamics and functions will be discussed in broader terms. Likewise, the mechanisms that drive the biogenesis of intralumenal membranes, including ESCRTs, will also be discussed, as well as their diverse composition and fate, including degradation in lysosomes and secretion as exosomes. This review will also discuss how intralumenal membranes are hijacked by pathogenic agents during intoxication and infection, and what is the biochemical composition and function of the intra-endosomal lumenal milieu. Finally, this review will allude to the size limitations imposed on intralumenal vesicle functions and speculate on the possible role of LBPA as calcium chelator in the acidic calcium stores of endo-lysosomes.
Topics: Animals; Cholesterol; Endocytosis; Endosomes; Lysophospholipids; Lysosomes; Multivesicular Bodies
PubMed: 31854087
DOI: 10.1111/tra.12715 -
BioMed Research International 2019Exosomes, the smallest vesicles (30-100 nm) among multivesicular bodies, are released by all body cells including tumor cells. The cargo they transfer plays an... (Review)
Review
Exosomes, the smallest vesicles (30-100 nm) among multivesicular bodies, are released by all body cells including tumor cells. The cargo they transfer plays an important role in intercellular communication. Tumor-derived exosomes (TEXs) maintain interactions between cancer cells and the microenvironment. Emerging evidence suggests that tumor cells release a large number of exosomes, which may not only influence proximal tumor cells and stromal cells in the local microenvironment but can also exert systemic effects as they are circulating in the blood. TEXs have been shown to boost tumor growth promote progression and metastatic spread via suppression or modification of the immune response towards cancer cells, regulation of tumor neo-angiogenesis, pre-metastatic niche formation, and therapy resistance. In addition, recent studies in patients with cancer suggest that TEXs could serve as tumor biomarker reflecting partially the genetic and molecular content of the parent cancer cell (i.e., as a so-called "liquid biopsy"). Furthermore, recent studies have demonstrated that exosomes may have immunotherapeutic applications, or can act as a drug delivery system for targeted therapies with drugs and biomolecules.
Topics: Biomarkers, Tumor; Disease Progression; Exosomes; Humans; Neoplasms; Neoplastic Cells, Circulating
PubMed: 31915681
DOI: 10.1155/2019/1628029 -
Traffic (Copenhagen, Denmark) Jan 2005In eukaryotic cells, delivery of transmembrane proteins into the lumen of the lysosome for degradation is mediated by the multivesicular body pathway. The function of... (Review)
Review
In eukaryotic cells, delivery of transmembrane proteins into the lumen of the lysosome for degradation is mediated by the multivesicular body pathway. The function of the ESCRT protein complexes is required for both the formation of multivesicular body lumenal vesicles and the sorting of endosomal cargo proteins into these vesicles. Recent studies have identified additional factors that seem to function as an upstream cargo retention system feeding into the ESCRT machinery, given new insights into the dynamic structure of multivesicular bodies, and identified a potential mechanism for multivesicular body vesicle formation.
Topics: Animals; Endosomes; Eukaryotic Cells; Humans; Lysosomes; Models, Biological; Protein Transport; Ubiquitin; Vacuoles; Vesicular Transport Proteins
PubMed: 15569240
DOI: 10.1111/j.1600-0854.2004.00246.x -
Cellular and Molecular Life Sciences :... Dec 2012Proteins of the ESCRT (endosomal sorting complex required for transport) complex function in membrane fission processes, such as multivesicular body (MVBs) formation,... (Review)
Review
Proteins of the ESCRT (endosomal sorting complex required for transport) complex function in membrane fission processes, such as multivesicular body (MVBs) formation, the terminal stages of cytokinesis, and separation of enveloped viruses from the plasma membrane. In mammalian cells, the machinery consists of a network of more than 20 proteins, organized into three complexes (ESCRT-I, -II, and -III), and other associated proteins such as the ATPase vacuolar protein sorting 4 (Vps4). Early biochemical studies of MVBs biogenesis in yeast support a model of sequential recruitment of ESCRT complexes on membranes. Live-cell imaging of ESCRT protein dynamics during viral budding and cytokinesis now reveal that this long-standing model of sequential assembly and disassembly holds true in mammalian cells.
Topics: Cell Membrane; Cytokinesis; Endosomal Sorting Complexes Required for Transport; HIV-1; HeLa Cells; Humans; Models, Biological; Multivesicular Bodies; Virus Release
PubMed: 22669260
DOI: 10.1007/s00018-012-1035-0 -
Molecular Microbiology Jun 2022Human cytomegalovirus (HCMV) is a ubiquitous herpesvirus and the leading cause of congenital disabilities as well as a significant cause of disease in immunocompromised... (Review)
Review
Human cytomegalovirus (HCMV) is a ubiquitous herpesvirus and the leading cause of congenital disabilities as well as a significant cause of disease in immunocompromised patients. The envelopment and egress of HCMV particles is an essential step of the viral life cycle as it determines viral spread and potentially tropism. Here we review the current literature on HCMV envelopment and egress with a particular focus on the role of virus-containing multivesicular body-like vesicles for virus egress and spread. We discuss the difficulties of determining the cellular provenance of these structures in light of viral redistribution of cellular marker proteins and provide potential paths to illuminate their genesis. Finally, we discuss how divergent egress pathways could result in virions of different tropisms.
Topics: Cytomegalovirus; Humans; Proteins; Virion; Virus Assembly
PubMed: 35607767
DOI: 10.1111/mmi.14946 -
Frontiers in Plant Science 2018In eukaryotic cells, the endomembrane system consists of multiple membrane-bound organelles, which play essential roles in the precise transportation of various cargo...
In eukaryotic cells, the endomembrane system consists of multiple membrane-bound organelles, which play essential roles in the precise transportation of various cargo proteins. In plant cells, vacuoles are regarded as the terminus of catabolic pathways whereas the selection and transport of vacuolar cargoes are mainly mediated by two types of organelles, multivesicular bodies (MVBs) also termed prevacuolar compartments (PVCs) and autophagosomes. MVBs are single-membrane bound organelles with intraluminal vesicles and mediate the transport between the Golgi network (TGN) and vacuoles, while autophagosomes are double-membrane bound organelles, which mediate cargo delivery to the vacuole for degradation and recycling during autophagy. Great progress has been achieved recently in identification and characterization of the conserved and plant-unique regulators involved in the MVB and autophagosome pathways. In this review, we present an update on the current knowledge of these key regulators and pay special attention to their conserved protein domains. In addition, we discuss the possible interplay between the MVB and autophagosome pathways in regulating vacuolar degradation in plants.
PubMed: 30619408
DOI: 10.3389/fpls.2018.01837 -
Proceedings of the National Academy of... Aug 2023Cataract is a leading ocular disease causing global blindness. The mechanism of cataractogenesis has not been well defined. Here, we demonstrate that the heat shock...
Cataract is a leading ocular disease causing global blindness. The mechanism of cataractogenesis has not been well defined. Here, we demonstrate that the heat shock protein 90β (HSP90β) plays a fundamental role in suppressing cataractogenesis. HSP90β is the most dominant HSP in normal lens, and its constitutive high level of expression is largely derived from regulation by Sp1 family transcription factors. More importantly, HSP90β is significantly down-regulated in human cataract patients and in aging mouse lenses, whereas HSP90β silencing in zebrafish causes cataractogenesis, which can only be rescued by itself but not other HSP90 genes. Mechanistically, HSP90β can directly interact with CHMP4B, a newly-found client protein involved in control of cytokinesis. HSP90β silencing causes upregulation of CHMP4B and another client protein, the tumor suppressor p53. CHMP4B upregulation or overexpression induces excessive division of lens epithelial cells without proper differentiation. As a result, these cells were triggered to undergo apoptosis due to activation of the p53/Bak-Bim pathway, leading to cataractogenesis and microphthalmia. Silence of both HSP90β and CHMP4B restored normal phenotype of zebrafish eye. Together, our results reveal that HSP90β is a critical inhibitor of cataractogenesis through negative regulation of CHMP4B and the p53-Bak/Bim pathway.
Topics: Animals; Humans; Mice; Aging; Cataract; Endosomal Sorting Complexes Required for Transport; HSP90 Heat-Shock Proteins; Multivesicular Bodies; Tumor Suppressor Protein p53; Zebrafish
PubMed: 37487085
DOI: 10.1073/pnas.2221522120