Phenylalalnyl-tRNA synthetase (PheRS), a member of class II aminoacyl-tRNA synthetases, catalyzes the synthesis of phenylalanyl-tRNAPhe (Phe-tRNAPhe). Hence, like other aminoacyl-tRNA synthetases, PheRS also plays a crucial role in the cellular translation process. Structural characterization demonstrates remarkable architectural diversity ranging from monomer to hetero-oligomer. Heterotetrameric PheRS contains an editing domain to proofread misincorporation of non-cognate amino acids. However, editing activity is absent in monomeric PheRS. PheRS has also shown some noncanonical functions, such as DNA binding properties, suggesting its involvement in complex regulatory pathways. Engineered mutants with relaxed substrate specificities of PheRS can be a promising tool for chemical and synthetic biology. Because of substantial structural variations among species due to evolutionary divergence, PheRS may be validated as a novel drug target. Human PheRS gene mutations have recently been implicated in several neurological disorders prompting structure-function studies to elucidate the molecular role of PheRS in such pathologies. In this review on PheRS, we will briefly cover all of the aforementioned aspects and our current understanding about the enzyme.
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Accumulating evidence suggests that telomeres may be a marker for biological aging and telomere length may be affected by multifactorial influences, including cumulative exposure to depression. Associations with telomere length have been reported for major depressive disorder, lifetime duration of depression, higher depression severity, and history of depression. The exact underling mechanisms for these associations have yet to be fully elucidated; however, oxidative stress, chronic inflammation, dysregulated hypothalamus-pituitary-adrenal axis, and altered cortisol levels may be important biochemical mediators. These mediators could also be influenced by psychological stress, unhealthy lifestyle behaviors, or other potential factors, such as childhood abuse, post-traumatic stress disorder, and anxiety that are commonly associated with depression. As such, stress reduction and lifestyle interventions that may affect the telomere maintenance system should be considered for individuals with depression.
: Nowadays, it is beyond doubt that synonymous codons are not the same with respect to expression of a gene. In favor of this, ribosome profiling experiments in vivo and in vitro have suggested that ribosome occupancy time is not the same for different synonymous codons. Therefore, synonymous codons influence differently the speed of translation elongation, which guides further cotranslational folding kinetics of a protein. It is now realized that the position of each codon in a coding sequence is important. The effect of synonymous codons on protein structure is an exciting field of research nowadays. This review discusses the recent develop-ments in this field.
LL-37, a cationic antimicrobial peptide, has numerous immune-modulating effects. However, the identity of a receptor(s) mediating the responses in immune cells remains uncertain. We have recently demonstrated that LL-37 interacts with the αMI-domain of integrin αMβ2 (Mac-1), a major receptor on the surface of myeloid cells, and induces a migratory response in Mac-1-expressing monocyte/macrophages as well as activation of Mac-1 on neutrophils. Here, we show that LL-37 and its C-terminal derivative supported strong adhesion of various Mac-1-expressing cells, including HEK293 cells stably transfected with Mac-1, human U937 monocytic cells and murine IC-21 macrophages. The cell adhesion to LL-37 was partially inhibited by specific Mac-1 antagonists, including mAb against the αM integrin subunit and neutrophil inhibitory factor, and completely blocked when anti-Mac-1 antibodies were combined with heparin, suggesting that cell surface heparan sulfate proteoglycans act cooperatively with integrin Mac-1. Coating both Gram-negative and Gram-positive bacteria with LL-37 significantly potentiated their phagocytosis by macrophages, and this process was blocked by a combination of anti-Mac-1 mAb and heparin. Furthermore, phagocytosis by wild-type murine peritoneal macrophages of LL-37-coated latex beads, a model of foreign surfaces, was several fold higher than that of untreated beads. By contrast, LL-37 failed to augment phagocytosis of beads by Mac-1-deficient macrophages. These results identify LL-37 as a novel ligand for integrin Mac-1 and demonstrate that the interaction between Mac-1 on macrophages and bacteria-bound LL-37 promotes phagocytosis.
Botulinum neurotoxins (BoNTs), the most potent toxins known to mankind, are metalloproteases that act on nerve–muscle junctions to block exocytosis through a very specific and exclusive endopeptidase activity against soluble N -ethylmaleimide-sensitive factor attachment protein receptor (SNARE) proteins of presynaptic vesicle fusion machinery. This very ability of the toxins to produce flaccid muscle paralysis through chemical denervation has been put to good use, and these potentially lethal toxins have been licensed to treat an ever expanding list of medical disorders and more popularly in the field of esthetic medicine. In most cases, therapeutic BoNT preparations are high-molecular-weight protein complexes consisting of BoNT, complexing proteins, and excipients. There is at least one isolated BoNT, which is free of complexing proteins in the market (Xeomin ® ). Each commercially available BoNT formulation is unique, differing mainly in molecular size and composition of complexing proteins, biological activity, and antigenicity. BoNT serotype A is marketed as Botox ® , Dysport ® , and Xeomin ® , while BoNT type B is commercially available as Myobloc ® . Nerve terminal intoxication by BoNTs is completely reversible, and the duration of therapeutic effects of BoNTs varies for different serotypes. Depending on the target tissue, BoNTs can block the cholinergic neuromuscular or cholinergic autonomic innervation of exocrine glands and smooth muscles. Therapeutic BoNTs exhibit a high safety and very limited adverse effects profile. Despite their established efficacy, the greatest concern with the use of therapeutic BoNTs is their propensity to elicit immunogenic reactions that might render the patient unresponsive to subsequent treatments, particularly in chronic conditions that might lead to long-term treatment and frequent injections. Keywords: botulinum neurotoxins, therapeutics, esthetics, botox, dysport, xeomin
Prion diseases are infectious, predominantly fatal neurodegenerative diseases characterized by abnormal prion protein (PrP) accumulation and neuronal loss. Studies on experimental animal models and clinical features of human prion diseases have shown unfolded PrP accumulation results in endoplasmic reticulum (ER) stress. While ER stress-mediated apoptosis is responsible for neuronal loss in prion diseases, ER stress also activates the unfolded protein response (UPR) in an effort to restore ER homeostasis. Of the UPR signaling pathways, the PERK-eIF2a pathway is implicated in the pathogenesis of prion diseases. The proteasome protein degradation system is also activated during the UPR. Increasing evidence indicates that proteasome and autophagy activities are affected in prion diseases. These findings suggest that ER stress/UPR contributes to the onset of prion diseases. Hence, strategies that target the ER are useful approaches in treating prion diseases. Additionally, immunotherapeutic approaches for prion diseases have been developed in recent decades. Single-chain fragment variable antibodies targeting the accumulation of PrP are also beneficial in the prevention of abnormal PrP propagation. This review discusses pathogenic mechanisms related to the ER and potential strategies for treating prion diseases.
Nasu-Hakola disease or polycystic lipomembranous osteodysplasia with sclerosing leukoencephalopathy (PLOSL) is a rare recessively inherited disease that is associated with early dementia and bone cysts with fractures. Here, we review the genetic causes of PLOSL with loss-of-function mutations or deletions in one of two genes, TYROBP and TREM2, encoding for two proteins DNAX-activating protein 12 (DAP12) and triggering receptor expressed on myeloid cells-2 (TREM2). TREM2 and DAP12 form an immunoreceptor signaling complex that mediates myeloid cell, including microglia and osteoclasts, development, activation, and function. Functionally, TREM2-DAP12 mediates osteoclast multi-nucleation, migration, and resorption. In microglia, TREM2-DAP12 participates in recognition and apoptosis of neuronal debris and amyloid deposits. Review of the complex immunoregulatory roles of TREM2-DAP12 in the innate immune system, where it can both promote and inhibit pro-inflammatory responses, is given. Little is known about the function of TREM2-DAP12 in normal brain homeostasis or in pathological central nervous system diseases. Based on the state of the field, genetic testing now aids in diagnosis of PLOSL, but therapeutics and interventions are still under development.
Botulinum neurotoxins (BoNTs), the most potent toxins known to mankind, are metal-loproteases that act on nerve-muscle junctions to block exocytosis through a very specific and exclusive endopeptidase activity against soluble N-ethylmaleimide-sensitive factor attachment protein receptor (SNARE) proteins of presynaptic vesicle fusion machinery. This very ability of the toxins to produce flaccid muscle paralysis through chemical denervation has been put to good use, and these potentially lethal toxins have been licensed to treat an ever expanding list of medical disorders and more popularly in the field of esthetic medicine. In most cases, therapeutic BoNT preparations are high-molecular-weight protein complexes consisting of BoNT, complexing proteins, and excipients. There is at least one isolated BoNT, which is free of complexing proteins in the market (Xeomin (R)). Each commercially available BoNT formulation is unique, differing mainly in molecular size and composition of complexing proteins, biological activity, and antigenicity. BoNT serotype A is marketed as Botox (R), Dysport (R), and Xeomin (R), while BoNT type B is commercially available as Myobloc (R). Nerve terminal intoxication by BoNTs is completely reversible, and the duration of therapeutic effects of BoNTs varies for different serotypes. Depending on the target tissue, BoNTs can block the cholinergic neuromuscular or cholinergic autonomic innervation of exocrine glands and smooth muscles. Therapeutic BoNTs exhibit a high safety and very limited adverse effects profile. Despite their established efficacy, the greatest concern with the use of therapeutic BoNTs is their propensity to elicit immunogenic reactions that might render the patient unresponsive to subsequent treatments, particularly in chronic conditions that might lead to long-term treatment and frequent injections.
The TRAMP complex assists the nuclear exosome to degrade a broad range of ribonucleic acid (RNA) substrates by increasing both exoribonucleolytic activity and substrate specificity. However, how the interactions between the TRAMP subunits and the components of the nuclear exosome regulate their functions in RNA degradation and substrate specificity remain unclear. This review aims to provide a summary of the recent findings on the role of the TRAMP complex in nuclear RNA degradation. The new insights from recent structural biological studies are discussed.
Huntington's disease (HD) is an autosomal dominant neurodegenerative disorder marked by chorea, dystonia, incoordination, and cognitive and motor disturbance. The major cause of HD is the cytotoxicity of the mutant huntingtin protein (mHTT), encoded by the mutant HTT gene. The mechanism by which mHTT leads to cytotoxicity and neuronal death is unclear, and thus enhancing clearance of the mHTT protein is likely to be an effective approach to treat HD. We have recently identified NUB1 (negative regulator of ubiquitin-like proteins 1) as a modifier of mHTT levels via enhancement of its proteasomal degradation. In this review, we will discuss the mechanism of NUB1-mediated mHTT clearance and potential targeting strategies.
The growth-associated protein, GAP-43 (also known as F1, neuromodulin, B-50), participates in the developmental regulation of axonal growth and neural network formation via protein kinase C-mediated regulation of cytoskeletal elements. Transgenic overexpression of GAP-43 can result in the formation of new synapses, neurite outgrowth, and synaptogenesis after injury. In a number of adult mammalian species, GAP-43 has been implicated in the regulation of synaptic transmission and plasticity, such as long-term potentiation, drug sensitization, and changes in memory processes. This review examines the molecular and biochemical attributes of GAP-43, its distribution in the central nervous system, subcellular localization, role in neurite outgrowth and development, and functions related to plasticity, such as those occurring during long-term potentiation, memory formation, and drug sensitization.
Capsaicin is the major capsaicinoid in chili peppers and is widely used as a spice. It is also used for topical applications in cases of peripheral neuropathy. The present study deals with its role in modulation of gamma radiation-induced damages of the biochemical constituents of rat liver mitochondrial membrane (RLM) preparation. The extent of lipid hydroperoxide formation, depletion in protein thiols, and formation of protein carbonyls have been biochemi- cally assessed in the presence of varying concentrations of capsaicin in RLM. Decrease in the activities of the important antioxidant enzyme superoxide dismutase, which is involved in the scavenging of free radicals, and the mitochondrial marker enzyme succinate dehydrogenase have been also looked into. Capsaicin has been found to efficiently inhibit radiation-induced biochemical alterations, namely lipid peroxidation and protein oxidation. It also significantly prevented radiation-induced loss in the activity of antioxidant enzyme and the important endog- enous antioxidant glutathione. The study suggests that capsaicin can act as an antioxidant and radioprotector in physiological systems.
DNA methylation is a fundamental biochemical modification that in conjunction with noncoding RNAs, histone modifications, and chromatin remodeling institutes the epigenetic machinery of mammalian cells. As a result of the second decade of intense epigenetic research and its role in human disease, substantial new mechanisms have been uncovered. However, it is well acknowledged that we have just scratched the tip of the iceberg. Epigenetic deregulation appears to be one of the foundations of major human diseases, including lung cancer, which is the most frequent cause of cancer-related deaths. Currently, significant effort is made to dissect the role of epigenetic deregulation in the development of lung cancer and utilize this knowledge in diagnostic and therapeutic applications. Taking advantage of the recent technologies in genomic research, many studies have been conducted to discover and validate abnormal DNA methylation patterns that may shed light on cancer development pathways and open new areas of potential clinical exploitation. In this article, we provide basic information of the DNA methylation involved in gene regulation and review the latest literature on potential relevant translational applications in lung cancer. Particular emphasis is given to the development and validation of DNA methylation biomarkers that may assist in the clinical management of lung cancer.
The past decade has seen an extraordinary explosion of research in the field of extracellular vesicles, especially in a specific type of extracellular vesicles originating from endosomal compartments, called exosomes. Exosomes are a specific subtype of secreted vesicles that are defined as small (similar to 30-120 nm) but very stable membrane vesicles that are released from a wide range of cells, including normal and cancer cells. As the content of exosomes is cell type specific, it is believed that they are a "fingerprint" of the releasing cell and its metabolic status. We hypothesized that the exosomes and their specific exosomal content (eg, microribonucleic acid) represent a precious biomedical tool and may be used as biomarkers for the diagnosis and prognosis of malignant tumors. In addition, exosomes may modify the phenotype of the parent and/or target cell by transferring pro-oncogenic molecules to induce cancerous phenotype of recipient cells and contribute to the formation of the premetastatic niche. The mechanism involved in these phenomena remains unclear; however, inclusion of signaling mediators into exosomes or exosome release may reduce their intracellular bioavailability in the parent cell, thereby altering cell phenotype and their metastatic potential. The aim of this review therefore is to analyze the biogenesis and role of exosomes from tumor cells, focusing primarily on ovarian cancer. Ovarian cancer is the most lethal gynecologic cancer, and an effective early diagnosis has the potential to improve patient survival. Ovarian cancer currently lacks a reliable method for early detection, however, exosomes have received great attention as potential biomarkers and mediators of the disease.
Hypoxia-inducible factor-1 (HIF-1) is responsible for cellular adaptations to hypoxia. While oxygen (O-2) negatively regulates its stability, many other factors affect HIF-1 stability and activity, including nitric oxide (NO). NO derived from l-arginine and nitrite (NO2-) could nitrosylate or nitrate HIF-1 and multiple proteins involved in HIF-1 regulation, and can allow HIF-1 to escape normoxic degradation. In turn, HIF-1 can increase NO production through multiple mechanisms, including increased inducible nitric oxide synthase (iNOS) expression and subunit 4-2 of cytochrome c oxidase (COX4-2) expression. There is therefore a high degree of crosstalk between HIF-1 and NO signaling. As such, many cellular responses to NO are mediated by HIF-1, and vice versa. This includes, but is not limited to, angiogenesis, apoptosis, senescence, and metabolic changes. These pathways all have important functions in normal physiology and when altered can contribute or, in some cases, lead to pathogenesis.
Septins embrace a large family of proteins highly conserved among eukaryotic species. They were originally identified in budding yeast in the early 1970s as proteins essential for completion of cytokinesis. In humans, septins comprise a group of 13 genes, most of which are present in several isoform variants, leading to a complex pattern of expression. The biological functions achieved by septins have been extensively investigated in yeast, and while several questions remain unanswered, details on the mechanisms of action and pathways relative to their major role in orchestrating the mitotic process, cell polarity, and diffusion barriers have been elucidated. In mammalian cells, the biological processes in which septins play important roles are emerging as increasingly complex. Septins are found with a broad range of expression in most tissues, and like in yeast, are essential for the successful completion of cytokinesis and for the establishment of cell polarity and diffusion barriers. However, they have also been shown to be important for phagocytosis and migration. Owing to their widespread expression in most mammalian cell subtypes and the plethora of functions to which they have been associated, it is not surprising that septins have been implicated in a large variety of human diseases. This review summarizes the current knowledge of septins' cellular functions and the mechanisms of regulation of their assembly. In addition, we present the broad range of human diseases where septins have been shown to be important for the etiology of the disease, including areas where septins have been recently implemented as biomarkers. Because of the growing evidence supporting the association of septins with novel cellular and biological functions, we expect this intriguing family of cytoskeletal interacting proteins to become coupled with an increasing number of human diseases.
The p21-activated kinase (PAK) family of serine/threonine protein kinases are downstream effectors of the Rho family of GTPases. PAKs are frequently upregulated in human diseases, including various cancers, and their overexpression correlates with disease progression. Current research findings have validated important roles for PAKs in cell proliferation, survival, gene transcription, transformation, and cytoskeletal remodeling. PAKs are shown to act as a converging node for many signaling pathways that regulate these cellular processes. Therefore, PAKs have emerged as attractive targets for treatment of disease. This review discusses the physiological and pathological roles of PAKs, validation of PAKs as new promising drug targets, and current challenges and advances in the development of PAK-targeted anticancer therapy, with a focus on PAKs and human cancers.
With the classification first proposed by the Bornstein group in 1995, matricellular proteins represent a diverse and expanding class of molecules that contribute to cell phenotype and regulate interactions with the extracellular matrix. Based on initial analysis, matricellular protein expression was thought to be limited to development, but in the intervening 20 years it has become apparent that it plays a pivotal role during healing in several different tissue types. Furthermore, while considered to modulate cell behavior, it is now apparent that matricellular proteins also function in the organization and crosslinking of the extracellular matrix during healing. The focus of this review is to discuss matricellular proteins in the context of skin healing, which in healthy individuals occurs through four overlapping temporal phases. We will also discuss matricellular proteins as potential therapeutics for the treatment of impaired skin healing.
Autophagy is an important and highly conserved catabolic process with roles in development, homeostasis, and cellular stress responses. It describes various distinct pathways for the delivery of cytoplasmic materials (including misfolded protein aggregates and some organelles) to the lysosome for degradation and component recycling. The best understood form of autophagy (macroautophagy) describes the de novo assembly, maturation, and trafficking of a unique double membrane-bound organelle - the autophagosomes - that sequesters cytoplasmic materials and ultimately merges with the lysosomal compartment to form a degradative autolysosome. To rapidly assemble such a structure in response to stimuli, cells express a family of dedicated autophagy-related (ATG) gene products that act sequentially to control membrane events leading first to the nucleation of an isolation membrane or phagophore, followed by phagophore expansion, and sealing to form an autophagosome that traffics to - and ultimately fuses with - the lysosome. These molecules are activated in response to upstream signaling pathways (notably, the mechanistic target of rapamycin [mTOR] pathway), and comprise protein and lipid kinases, putative membrane coats, and unique ubiquitin-like conjugation systems. In concert, a barrage of accessory proteins involved in various membrane trafficking pathways focused on the endosomal compartment are co-opted at the assembly site to facilitate autophagosome biogenesis. Understanding the integrated pathways that coordinate autophagosome assembly at the molecular level will be crucial if we are to realize the potential for autophagy manipulation in future disease therapies.
