Molecular Functions of Glycoconjugates in Autophagy.
Ontology highlight
ABSTRACT: Glycoconjugates, glycans, carbohydrates, and sugars: these terms encompass a class of biomolecules that are diverse in both form and function ranging from free oligosaccharides, glycoproteins, and proteoglycans, to glycolipids that make up a complex glycan code that impacts normal physiology and disease. Recent data suggest that one mechanism by which glycoconjugates impact physiology is through the regulation of the process of autophagy. Autophagy is a degradative pathway necessary for differentiation, organism development, and the maintenance of cell and tissue homeostasis. In this review, we will highlight what is known about the regulation of autophagy by glycoconjugates focusing on signaling mechanisms from the extracellular surface and the regulatory roles of intracellular glycans. Glycan signaling from the extracellular matrix converges on "master" regulators of autophagy including AMPK and mTORC1, thus impacting their localization, activity, and/or expression. Within the intracellular milieu, gangliosides are constituents of the autophagosome membrane, a subset of proteins composing the autophagic machinery are regulated by glycosylation, and oligosaccharide exposure in the cytosol triggers an autophagic response. The examples discussed provide some mechanistic insights into glycan regulation of autophagy and reveal areas for future investigation.
Project description:Carbohydrates and glycoconjugates have been shown to exert pro-inflammatory effects on the dendritic cells (DCs), supporting pathogen-induced innate immunity and antigen processing, as well as immunosuppressive effects in the tolerance to self-proteins. Additionally, the innate inflammatory response to implanted biomaterials has been hypothesized to be mediated by inflammatory cells interacting with adsorbed proteins, many of which are glycosylated. However, the molecular factors relevant for surface displayed glycoconjugate modulation of dendritic cell (DC) phenotype are unknown. Thus, in this study, a model system was developed to establish the role of glycan composition, density, and carrier cationization state on DC response. Thiol modified glycans were covalently bound to a model protein carrier, maleimide functionalized bovine serum albumin (BSA), and the number of glycans per BSA modulated. Additionally, the carrier isoelectric point was scaled from a pI of ∼4.0 to ∼10.0 using ethylenediamine (EDA). The DC response to the neoglycoconjugates adsorbed to wells of a 384-well plate was determined via a high throughput assay. The underlying trends in DC phenotype in relation to conjugate properties were elucidated via multivariate general linear models. It was found that glycoconjugates with more than 20 glycans per carrier had the greatest impact on the pro-inflammatory response from DCs, followed by conjugates having an isoelectric point above 9.5. Surfaces displaying terminal α1-2 linked mannose structures were able to increase the inflammatory DC response to a greater extent than did any other terminal glycan structure. The results herein can be applied to inform the design of the next generation of combination products and biomaterials for use in future vaccines and implanted materials.
Project description:The etiology of hearing impairment following cochlear damage can be caused by many factors, including congenital or acquired onset, ototoxic drugs, noise exposure, and aging. Regardless of the many different etiologies, a common pathologic change is auditory cell death. It may be difficult to explain hearing impairment only from the aspect of cell death including apoptosis, necrosis, or necroptosis because the level of hearing loss varies widely. Therefore, we focused on autophagy as an intracellular phenomenon functionally competing with cell death. Autophagy is a dynamic lysosomal degradation and recycling system in the eukaryotic cell, mandatory for controlling the balance between cell survival and cell death induced by cellular stress, and maintaining homeostasis of postmitotic cells, including hair cells (HCs) and spiral ganglion neurons (SGNs) in the inner ear. Autophagy is considered a candidate for the auditory cell fate decision factor, whereas autophagy deficiency could be one of major causes of hearing impairment. In this paper, we review the molecular mechanisms and biologic functions of autophagy in the auditory system and discuss the latest research concerning autophagy-related genes and sensorineural hearing loss to gain insight into the role of autophagic mechanisms in inner-ear disorders.
Project description:A new series of salicyl glycoconjugates containing hydrazide and hydrazone moieties were designed and synthesized. The bioassay indicated that the novel compounds had no in vitro fungicidal activity but showed significant in vivo antifungal activity against the tested fungal pathogens. Some compounds even had superior activity than the commercial fungicides in greenhouse trial. The results of RT-PCR analysis showed that the designed salicyl glycoconjugates could induce the expression of LOX1 and Cs-AOS2, which are the specific marker genes of jasmonate signaling pathway, to trigger the plant defense resistance.
Project description:Eosinophils are granule-containing leukocytes which develop in the bone marrow. For many years, eosinophils have been recognized as cytotoxic effector cells, but recent studies suggest that they perform additional immunomodulatory and homeostatic functions. Autophagy is a conserved intracellular process which preserves cellular homeostasis. Autophagy defects have been linked to the pathogenesis of many human disorders. Evidence for abnormal regulation of autophagy, including decreased or increased expression of autophagy-related (ATG) proteins, has been reported in several eosinophilic inflammatory disorders, such as Crohn's disease, bronchial asthma, eosinophilic esophagitis, and chronic rhinosinusitis. Despite the increasing extent of research using preclinical models of immune cell-specific autophagy deficiency, the physiological relevance of autophagic pathway in eosinophils has remained unknown until recently. Owing to the increasing evidence that eosinophils play a role in keeping organismal homeostasis, the regulation of eosinophil functions is of considerable interest. Here, we discuss the most recent advances on the role of autophagy in eosinophils, placing particular emphasis on insights obtained in mouse models of infections and malignant diseases in which autophagy has genetically dismantled in the eosinophil lineage. These studies pointed to the possibility that autophagy-deficient eosinophils exaggerate inflammation. Therefore, the pharmacological modulation of the autophagic pathway in these cells could be used for therapeutic interventions.
Project description:A facile, high yielding access to rare chimeric compounds combining phosphorus ylides with complex glycosyl formamides is described. We determined x-ray structures gaining structural insight into this compounds class. In addition, data mining of similar compounds deposited within the Cambridge Structural Database was performed. These derivatives could be used either as synthetic intermediates via the ylide functionalization and glyco chemical biology synthons or improving the pharmacokinetic properties of a potential bioactive molecule, exploiting the glycosyl moiety.
Project description:Glycoconjugates are the most diverse biomolecules of life. Mostly located at the cell surface, they translate into cell-specific "barcodes" and offer a vast repertoire of functions, including support of cellular physiology, lifestyle, and pathogenicity. Functions can be fine-tuned by non-carbohydrate modifications on the constituting monosaccharides. Among these modifications is pyruvylation, which is present either in enol or ketal form. The most commonly best-understood example of pyruvylation is enol-pyruvylation of N-acetylglucosamine, which occurs at an early stage in the biosynthesis of the bacterial cell wall component peptidoglycan. Ketal-pyruvylation, in contrast, is present in diverse classes of glycoconjugates, from bacteria to algae to yeast-but not in humans. Mild purification strategies preventing the loss of the acid-labile ketal-pyruvyl group have led to a collection of elucidated pyruvylated glycan structures. However, knowledge of involved pyruvyltransferases creating a ring structure on various monosaccharides is scarce, mainly due to the lack of knowledge of fingerprint motifs of these enzymes and the unavailability of genome sequences of the organisms undergoing pyruvylation. This review compiles the current information on the widespread but under-investigated ketal-pyruvylation of monosaccharides, starting with different classes of pyruvylated glycoconjugates and associated functions, leading to pyruvyltransferases, their specificity and sequence space, and insight into pyruvate analytics.
Project description:Prokaryotic glycosylation fulfills an important role in maintaining and protecting the structural integrity and function of the bacterial cell wall, as well as serving as a flexible adaption mechanism to evade environmental and host-induced pressure. The scope of bacterial and archaeal protein glycosylation has considerably expanded over the past decade(s), with numerous examples covering the glycosylation of flagella, pili, glycosylated enzymes, as well as surface-layer proteins. This article addresses structure, analysis, function, genetic basis, biosynthesis, and biomedical and biotechnological applications of cell-envelope glycoconjugates, S-layer glycoprotein glycans, and "nonclassical" secondary-cell wall polysaccharides. The latter group of polymers mediates the important attachment and regular orientation of the S-layer to the cell wall. The structures of these glycopolymers reveal an enormous diversity, resembling the structural variability of bacterial lipopolysaccharides and capsular polysaccharides. While most examples are presented for Gram-positive bacteria, the S-layer glycan of the Gram-negative pathogen Tannerella forsythia is also discussed. In addition, archaeal S-layer glycoproteins are briefly summarized.
Project description:PEX13 is an integral membrane protein on the peroxisome that regulates peroxisomal matrix protein import during peroxisome biogenesis. Mutations in PEX13 and other peroxin proteins are associated with Zellweger syndrome spectrum (ZSS) disorders, a subtype of peroxisome biogenesis disorder characterized by prominent neurological, hepatic, and renal abnormalities leading to neonatal death. The lack of functional peroxisomes in ZSS patients is widely accepted as the underlying cause of disease; however, our understanding of disease pathogenesis is still incomplete. Here, we demonstrate that PEX13 is required for selective autophagy of Sindbis virus (virophagy) and of damaged mitochondria (mitophagy) and that disease-associated PEX13 mutants I326T and W313G are defective in mitophagy. The mitophagy function of PEX13 is shared with another peroxin family member PEX3, but not with two other peroxins, PEX14 and PEX19, which are required for general autophagy. Together, our results demonstrate that PEX13 is required for selective autophagy, and suggest that dysregulation of PEX13-mediated mitophagy may contribute to ZSS pathogenesis.
Project description:Helminths are multicellular parasitic worms that comprise a major class of human pathogens and cause an immense amount of suffering worldwide. Helminths possess an abundance of complex and unique glycoconjugates that interact with both the innate and adaptive arms of immunity in definitive and intermediate hosts. These glycoconjugates represent a major untapped reservoir of immunomodulatory compounds, which have the potential to treat autoimmune and inflammatory disorders, and antigenic glycans, which could be exploited as vaccines and diagnostics. This review will survey current knowledge of the interactions between helminth glycans and host immunity and highlight the gaps in our understanding which are relevant to advancing therapeutics, vaccine development, and diagnostics.
Project description:Homeostatic maintenance of physiological functions is fundamental to organismal well-being. Disruption or imbalance in homeostasis results in functional disturbances at molecular, cellular, and tissue levels, leading to manifestation as physical and mental illnesses. Homeostatic imbalance is caused by a range of pathophysiological mechanisms, including disrupted reduction-oxidation reactions, inflammatory responses, metabolic disturbances, or failure in quality control of cellular proteins and organelles. However, the roles for the protein/organelle quality control in the regulation of behaviors, in particular of cognitive processes, had not been well documented, until recent reports finally supported this concept. The frontline studies in neuroscience have revealed that synaptic components (e.g., synaptic proteins, organelles, neurotransmitters and their receptors) are selectively degraded by autophagy, a cellular recycling machinery implicated in surveillance and quality control of proteins and organelles responsible for the maintenance of cellular homeostasis. Apart from the canonical role of autophagy in supporting cell viability, synaptic autophagy appears to regulate synapse remodeling and plasticity. Consistently, emerging evidence suggests novel roles of autophagy in memory encoding, information processing, or cognitive functions. In this review, we overview recent progress in understanding the roles of neuronal autophagy in homeostatic maintenance of synaptic functions, with particular focus on how disruptions in these processes may contribute to the pathophysiology of psychiatric disorders.