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Cell Sep 2019Long-distance RNA transport enables local protein synthesis at metabolically-active sites distant from the nucleus. This process ensures an appropriate spatial...
Long-distance RNA transport enables local protein synthesis at metabolically-active sites distant from the nucleus. This process ensures an appropriate spatial organization of proteins, vital to polarized cells such as neurons. Here, we present a mechanism for RNA transport in which RNA granules "hitchhike" on moving lysosomes. In vitro biophysical modeling, live-cell microscopy, and unbiased proximity labeling proteomics reveal that annexin A11 (ANXA11), an RNA granule-associated phosphoinositide-binding protein, acts as a molecular tether between RNA granules and lysosomes. ANXA11 possesses an N-terminal low complexity domain, facilitating its phase separation into membraneless RNA granules, and a C-terminal membrane binding domain, enabling interactions with lysosomes. RNA granule transport requires ANXA11, and amyotrophic lateral sclerosis (ALS)-associated mutations in ANXA11 impair RNA granule transport by disrupting their interactions with lysosomes. Thus, ANXA11 mediates neuronal RNA transport by tethering RNA granules to actively-transported lysosomes, performing a critical cellular function that is disrupted in ALS.
Topics: Amyotrophic Lateral Sclerosis; Animals; Animals, Genetically Modified; Annexins; Axonal Transport; Axons; Cell Line, Tumor; Cytoplasmic Granules; Female; Humans; Induced Pluripotent Stem Cells; Lysosomes; Male; Mutation; Protein Binding; RNA; Rats; Rats, Sprague-Dawley; Transfection; Zebrafish
PubMed: 31539493
DOI: 10.1016/j.cell.2019.08.050 -
The New Phytologist Jan 2011Annexins are multifunctional lipid-binding proteins. Plant annexins are expressed throughout the life cycle and are under environmental control. Their association or... (Review)
Review
Annexins are multifunctional lipid-binding proteins. Plant annexins are expressed throughout the life cycle and are under environmental control. Their association or insertion into membranes may be governed by a range of local conditions (Ca(2+), pH, voltage or lipid identity) and nonclassical sorting motifs. Protein functions include exocytosis, actin binding, peroxidase activity, callose synthase regulation and ion transport. As such, annexins appear capable of linking Ca(2+), redox and lipid signalling to coordinate development with responses to the biotic and abiotic environment. Significant advances in plant annexin research have been made in the past 2 yr. Here, we review the basis of annexin multifunctionality and suggest how these proteins may operate in the life and death of a plant cell.
Topics: Amino Acid Sequence; Annexins; Cytosol; Environment; Ion Transport; Lipid Metabolism; Molecular Sequence Data; Plant Proteins; Protein Processing, Post-Translational; Protein Structure, Tertiary; Protein Transport; Sequence Alignment
PubMed: 21083562
DOI: 10.1111/j.1469-8137.2010.03533.x -
JCI Insight Jul 2022Membrane instability and disruption underlie myriad acute and chronic disorders. Anxa6 encodes the membrane-associated protein annexin A6 and was identified as a genetic...
Membrane instability and disruption underlie myriad acute and chronic disorders. Anxa6 encodes the membrane-associated protein annexin A6 and was identified as a genetic modifier of muscle repair and muscular dystrophy. To evaluate annexin A6's role in membrane repair in vivo, we inserted sequences encoding green fluorescent protein (GFP) into the last coding exon of Anxa6. Heterozygous Anxa6gfp mice expressed a normal pattern of annexin A6 with reduced annexin A6GFP mRNA and protein. High-resolution imaging of wounded muscle fibers showed annexin A6GFP rapidly formed a repair cap at the site of injury. Injured cardiomyocytes and neurons also displayed repair caps after wounding, highlighting annexin A6-mediated repair caps as a feature in multiple cell types. Using surface plasmon resonance, we showed recombinant annexin A6 bound phosphatidylserine-containing lipids in a Ca2+- and dose-dependent fashion with appreciable binding at approximately 50 μM Ca2+. Exogenously added recombinant annexin A6 localized to repair caps and improved muscle membrane repair capacity in a dose-dependent fashion without disrupting endogenous annexin A6 localization, indicating annexin A6 promotes repair from both intracellular and extracellular compartments. Thus, annexin A6 orchestrates repair in multiple cell types, and recombinant annexin A6 may be useful in additional chronic disorders beyond skeletal muscle myopathies.
Topics: Animals; Annexin A6; Annexins; Calcium; Mice; Muscle, Skeletal; Myocytes, Cardiac
PubMed: 35866481
DOI: 10.1172/jci.insight.158107 -
International Journal of Molecular... Apr 2018Glaucoma is one of the leading causes of irreversible visual loss, which has been estimated to affect 3.5% of those over 40 years old and projected to affect a total of... (Review)
Review
Glaucoma is one of the leading causes of irreversible visual loss, which has been estimated to affect 3.5% of those over 40 years old and projected to affect a total of 112 million people by 2040. Such a dramatic increase in affected patients demonstrates the need for continual improvement in the way we diagnose and treat this condition. Annexin A5 is a 36 kDa protein that is ubiquitously expressed in humans and is studied as an indicator of apoptosis in several fields. This molecule has a high calcium-dependent affinity for phosphatidylserine, a cell membrane phospholipid externalized to the outer cell membrane in early apoptosis. The DARC (Detection of Apoptosing Retinal Cells) project uses fluorescently-labelled annexin A5 to assess glaucomatous degeneration, the inherent process of which is the apoptosis of retinal ganglion cells. Furthermore, this project has conducted investigation of the retinal apoptosis in the neurodegenerative conditions of the eye and brain. In this present study, we summarized the use of annexin A5 as a marker of apoptosis in the eye. We also relayed the progress of the DARC project, developing real-time imaging of retinal ganglion cell apoptosis in vivo from the experimental models of disease and identifying mechanisms underlying neurodegeneration and its treatments, which has been applied to the first human clinical trials. DARC has potential as a biomarker in neurodegeneration, especially in the research of novel treatments, and could be a useful tool for the diagnosis and monitoring of glaucoma.
Topics: Animals; Annexin A5; Annexins; Apoptosis; Biomarkers; Glaucoma; Humans; Retina; Retinal Ganglion Cells
PubMed: 29673196
DOI: 10.3390/ijms19041218 -
Cells Nov 2020Discovered over 40 years ago, the annexin proteins were found to be a structurally conserved subgroup of Ca-binding proteins. While the initial research on annexins...
Discovered over 40 years ago, the annexin proteins were found to be a structurally conserved subgroup of Ca-binding proteins. While the initial research on annexins focused on their signature feature of Ca-dependent binding to membranes, over the years the biennial Annexin conference series has highlighted additional diversity in the functions attributed to the annexin family of proteins. The roles of these proteins now extend from basic science to biomedical research, and are being translated into the clinic. The research on annexins involves a global network of researchers, and the 10th biennial Annexin conference brought together over 80 researchers from ten European countries, USA, Brazil, Singapore, Japan and Australia for 3 days in September 2019. In this conference, the discussions focused on two distinct themes-the role of annexins in cellular organization and in health and disease. The articles published in this Special Issue cover these two main themes discussed at this conference, offering a glimpse into some of the notable findings in the field of annexin biology.
Topics: Animals; Annexins; Autophagy; Disease; Health; Host-Pathogen Interactions; Humans; Inflammation; Triple Negative Breast Neoplasms
PubMed: 33202541
DOI: 10.3390/cells9112477 -
Genome Biology 2004Annexins are traditionally thought of as calcium-dependent phospholipid-binding proteins, but recent work suggests a more complex set of functions. More than a thousand... (Review)
Review
Annexins are traditionally thought of as calcium-dependent phospholipid-binding proteins, but recent work suggests a more complex set of functions. More than a thousand proteins of the annexin superfamily have been identified in major eukaryotic phyla, but annexins are absent from yeasts and prokaryotes. The unique annexin core domain is made up of four similar repeats approximately 70 amino acids long, each of which usually contains a characteristic 'type 2' motif for binding calcium ions. Animal and fungal annexins also have non-homologous amino-terminal domains of varying length and sequence, which are responsible for the distinct localizations and specialized functions of the proteins through post-translational modification and binding to other proteins. Annexins interact with various cell-membrane components that are involved in the structural organization of the cell, intracellular signaling by enzyme modulation and ion fluxes, growth control, and they can act as atypical calcium channels. Analysis of site-specific conservation in the core domain suggests a role for certain buried residues in the calcium-channel activity of vertebrate annexins and in the structural stability of their core domains. Evolutionarily significant differences between subfamilies are preferentially localized to accessible sites on the protein surface that determine membrane binding and interactions with cytosolic proteins.
Topics: Animals; Annexins; Humans
PubMed: 15059252
DOI: 10.1186/gb-2004-5-4-219 -
The FEBS Journal Oct 2008Annexins and S100 proteins represent two large, but distinct, calcium-binding protein families. Annexins are made up of a highly alpha-helical core domain that binds... (Review)
Review
Annexins and S100 proteins represent two large, but distinct, calcium-binding protein families. Annexins are made up of a highly alpha-helical core domain that binds calcium ions, allowing them to interact with phospholipid membranes. Furthermore, some annexins, such as annexins A1 and A2, contain an N-terminal region that is expelled from the core domain on calcium binding. These events allow for the interaction of the annexin N-terminus with target proteins, such as S100. In addition, when an S100 protein binds calcium ions, it undergoes a structural reorientation of its helices, exposing a hydrophobic patch capable of interacting with its targets, including the N-terminal sequences of annexins. Structural studies of the complexes between members of these two families have revealed valuable details regarding the mechanisms of the interactions, including the binding surfaces and conformation of the annexin N-terminus. However, other S100-annexin interactions, such as those between S100A11 and annexin A6, or between dicalcin and annexins A1, A2 and A5, appear to be more complicated, involving the annexin core region, perhaps in concert with the N-terminus. The diversity of these interactions indicates that multiple forms of recognition exist between S100 proteins and annexins. S100-annexin interactions have been suggested to play a role in membrane fusion events by the bridging together of two annexin proteins, bound to phospholipid membranes, by an S100 protein. The structures and differential interactions of S100-annexin complexes may indicate that this process has several possible modes of protein-protein recognition.
Topics: Animals; Annexins; Humans; Membrane Proteins; Multiprotein Complexes; Protein Binding; S100 Proteins
PubMed: 18795951
DOI: 10.1111/j.1742-4658.2008.06654.x -
Cells Aug 2021Annexin A1 is a 37 kDa phospholipid-binding protein that is expressed in many tissues and cell types, including leukocytes, lymphocytes and epithelial cells. Although... (Review)
Review
Annexin A1 is a 37 kDa phospholipid-binding protein that is expressed in many tissues and cell types, including leukocytes, lymphocytes and epithelial cells. Although Annexin A1 has been extensively studied for its anti-inflammatory activity, it has been shown that, in the cancer context, its activity switches from anti-inflammatory to pro-inflammatory. Remarkably, Annexin A1 shows pro-invasive and pro-tumoral properties in several cancers either by eliciting autocrine signaling in cancer cells or by inducing a favorable tumor microenvironment. Indeed, the signaling of the -terminal peptide of AnxA1 has been described to promote the switching of macrophages to the pro-tumoral M2 phenotype. Moreover, AnxA1 has been described to prevent the induction of antigen-specific cytotoxic T cell response and to play an essential role in the induction of regulatory T lymphocytes. In this way, Annexin A1 inhibits the anti-tumor immunity and supports the formation of an immunosuppressed tumor microenvironment that promotes tumor growth and metastasis. For these reasons, in this review we aim to describe the role of Annexin A1 in the establishment of the tumor microenvironment, focusing on the immunosuppressive and immunomodulatory activities of Annexin A1 and on its interaction with the epidermal growth factor receptor.
Topics: Animals; Annexin A1; Autocrine Communication; Humans; Immunity; Neoplasms; Tumor Microenvironment
PubMed: 34571894
DOI: 10.3390/cells10092245 -
Traffic (Copenhagen, Denmark) Aug 2004The actin cytoskeleton is a malleable framework of polymerised actin monomers that may be rapidly restructured to enable diverse cellular activities such as motility,... (Review)
Review
The actin cytoskeleton is a malleable framework of polymerised actin monomers that may be rapidly restructured to enable diverse cellular activities such as motility, endocytosis and cytokinesis. The regulation of actin dynamics involves the coordinated activity of numerous proteins, among which members of the annexin family of Ca2+- and phospholipid-binding proteins play an important role. Although the roles of annexins in actin dynamics are not understood at a mechanistic level, annexins have the requisite properties to integrate Ca2+-signaling with actin dynamics at membrane contact sites. In this review we discuss the current state of knowledge on this topic, and consider how and where annexins may fit into the complex molecular machinery that regulates the actin cytoskeleton.
Topics: Actins; Animals; Annexins; Calcium Signaling; Cell Membrane; Cytoskeleton; Humans; Models, Molecular
PubMed: 15260827
DOI: 10.1111/j.1600-0854.2004.00210.x -
Cell Adhesion & Migration May 2017
Topics: Animals; Annexins; Cell Adhesion; Cell Movement; Disease; Humans; Signal Transduction
PubMed: 28430001
DOI: 10.1080/19336918.2017.1321930