Coronavirus disease 2019 (COVID-19), a highly infectious disease caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has infected more than 235 million individuals and led to more ...than 4.8 million deaths worldwide as of October 5 2021. Cryo-electron microscopy and topology show that the SARS-CoV-2 genome encodes lots of highly glycosylated proteins, such as spike (S), envelope (E), membrane (M), and ORF3a proteins, which are responsible for host recognition, penetration, binding, recycling and pathogenesis. Here we reviewed the detections, substrates, biological functions of the glycosylation in SARS-CoV-2 proteins as well as the human receptor ACE2, and also summarized the approved and undergoing SARS-CoV-2 therapeutics associated with glycosylation. This review may not only broad the understanding of viral glycobiology, but also provide key clues for the development of new preventive and therapeutic methodologies against SARS-CoV-2 and its variants.
The Warburg effect, which originally described increased production of lactate in cancer, is associated with diverse cellular processes such as angiogenesis, hypoxia, polarization of macrophages and ...activation of T cells. This phenomenon is intimately linked to several diseases including neoplasia, sepsis and autoimmune diseases
. Lactate, which is converted from pyruvate in tumour cells, is widely known as an energy source and metabolic by-product. However, its non-metabolic functions in physiology and disease remain unknown. Here we show that lactate-derived lactylation of histone lysine residues serves as an epigenetic modification that directly stimulates gene transcription from chromatin. We identify 28 lactylation sites on core histones in human and mouse cells. Hypoxia and bacterial challenges induce the production of lactate by glycolysis, and this acts as a precursor that stimulates histone lactylation. Using M1 macrophages that have been exposed to bacteria as a model system, we show that histone lactylation has different temporal dynamics from acetylation. In the late phase of M1 macrophage polarization, increased histone lactylation induces homeostatic genes that are involved in wound healing, including Arg1. Collectively, our results suggest that an endogenous 'lactate clock' in bacterially challenged M1 macrophages turns on gene expression to promote homeostasis. Histone lactylation thus represents an opportunity to improve our understanding of the functions of lactate and its role in diverse pathophysiological conditions, including infection and cancer.
Of the 20 ribosomally coded amino acid residues, lysine is the most frequently post-translationally modified, which has important functional and regulatory consequences. Here we report the ...identification and verification of a previously unreported form of protein post-translational modification (PTM): lysine succinylation. The succinyllysine residue was initially identified by mass spectrometry and protein sequence alignment. The identified succinyllysine peptides derived from in vivo proteins were verified by western blot analysis, in vivo labeling with isotopic succinate, MS/MS and HPLC coelution of their synthetic counterparts. We further show that lysine succinylation is evolutionarily conserved and that this PTM responds to different physiological conditions. Our study also implies that succinyl-CoA might be a cofactor for lysine succinylation. Given the apparent high abundance of lysine succinylation and the significant structural changes induced by this PTM, it is expected that lysine succinylation has important cellular functions.
Gold-catalyzed reactions, which have been widely explored over the past several years, are powerful tools in organic synthesis to access complex molecular frameworks, and some corresponding excellent ...reviews have been reported. However, little attention has been paid to summarize the reactions of strained small-ring-containing molecules catalyzed by gold. This
critical review
mainly puts its emphasis on the recent progress in the field of gold-catalyzed transformations of cyclopropyl-, cyclopropenyl-, epoxy- and aziridinyl-containing molecules. The rapid construction of interesting building blocks in organic synthesis from strained small rings catalyzed by gold has been summarized in this review (106 references).
This review provides an overview of the recent progress in the field of gold-catalyzed transformations of strained small rings.
Short-chain fatty acids and their corresponding acyl-CoAs sit at the crossroads of metabolic pathways and play important roles in diverse cellular processes. They are also precursors for protein ...post-translational lysine acylation modifications. A noteworthy example is the newly identified lysine 2-hydroxyisobutyrylation （Khib） that is derived from 2-hydroxyisobutyrate and 2-hydroxyisobutyryl-CoA. Histone Khib has been shown to be associated with active gene expression in spermatogenic cells. However, the key elements that regulate this post-translational lysine acyla- tion pathway remain unknown. This has hindered characterization of the mechanisms by which this modification exerts its biological functions. Here we show that Esalp in budding yeast and its homologue Tip60 in human could add Khib to substrate proteins both in vitro and in vivo. In addition, we have identified HDAC2 and HDAC3 as the major enzymes to remove Khmb. Moreover, we report the first global profiling of Khib proteome in mammalian cells, identifying 6 548 Khb sites on 1 725 substrate proteins. Our study has thus discovered both the ＂writers＂ and ＂erasers＂ for histone Kh~b marks, and major Khib protein substrates. These results not only illustrate the landscape of this new lysine acylation pathway, but also open new avenues for studying diverse functions of cellular metabolites associated with this pathway.
Type 2 diabetes (T2D) is characterized by insulin resistance along with pancreatic β cell failure. β cell factors are traditionally thought to control glucose homeostasis by modulating insulin ...levels, not insulin sensitivity. Exosomes are emerging as new regulators of intercellular communication. However, the role of β-cell-derived exosomes in metabolic homeostasis is poorly understood. Here, we report that microRNA-26a (miR-26a) in β cells not only modulates insulin secretion and β cell replication in an autocrine manner but also regulates peripheral insulin sensitivity in a paracrine manner through circulating exosomes. MiR-26a is reduced in serum exosomes of overweight humans and is inversely correlated with clinical features of T2D. Moreover, miR-26a is down-regulated in serum exosomes and islets of obese mice. Using miR-26a knockin and knockout mouse models, we showed that miR-26a in β cells alleviates obesity-induced insulin resistance and hyperinsulinemia. Mechanistically, miR-26a in β cells enhances peripheral insulin sensitivity via exosomes. Meanwhile, miR-26a prevents hyperinsulinemia through targeting several critical regulators of insulin secretion and β cell proliferation. These findings provide a new paradigm for the far-reaching systemic functions of β cells and offer opportunities for the treatment of T2D.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Cancer-associated fibroblasts (CAFs) are the predominant components of the tumor microenvironment (TME) and influence cancer hallmarks, but without systematic investigation on their ubiquitous ...characteristics across different cancer types. Here, we perform pan-cancer analysis on 226 samples across 10 solid cancer types to profile the TME at single-cell resolution, illustrating the commonalities/plasticity of heterogenous CAFs. Activation trajectory of the major CAF types is divided into three states, exhibiting distinct interactions with other cell components, and relating to prognosis of immunotherapy. Moreover, minor CAF components represent the alternative origin from other TME components (e.g., endothelia and macrophages). Particularly, the ubiquitous presentation of endothelial-to-mesenchymal transition CAF, which may interact with proximal SPP1
tumor-associated macrophages, is implicated in endothelial-to-mesenchymal transition and survival stratifications. Our study comprehensively profiles the shared characteristics and dynamics of CAFs, and highlight their heterogeneity and plasticity across different cancer types. Browser of integrated pan-cancer single-cell information is available at https://gist-fgl.github.io/sc-caf-atlas/ .
Acetylation of histones at DNA regulatory elements plays a critical role in transcriptional activation. Histones are also modified by other acyl moieties, including crotonyl, yet the mechanisms that ...govern acetylation versus crotonylation and the functional consequences of this “choice” remain unclear. We show that the coactivator p300 has both crotonyltransferase and acetyltransferase activities, and that p300-catalyzed histone crotonylation directly stimulates transcription to a greater degree than histone acetylation. Levels of histone crotonylation are regulated by the cellular concentration of crotonyl-CoA, which can be altered through genetic and environmental perturbations. In a cell-based model of transcriptional activation, increasing or decreasing the cellular concentration of crotonyl-CoA leads to enhanced or diminished gene expression, respectively, which correlates with the levels of histone crotonylation flanking the regulatory elements of activated genes. Our findings support a general principle wherein differential histone acylation (i.e., acetylation versus crotonylation) couples cellular metabolism to the regulation of gene expression.
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•The histone acetyltransferase p300 also regulates histone crotonylation•Histone crotonylation directly stimulates transcription•Histone crotonylation is regulated by the concentration of crotonyl-CoA•Local changes in differential histone acylation influence gene expression
Sabari et al. establish a direct role for histone crotonylation in the stimulation of transcription and demonstrate that the modification is regulated enzymatically by p300/CBP and metabolically by the availability of crotonyl-CoA.
Dysregulation of amino acids is closely linked to the initiation and progression of sarcopenia. We summarized recent advancements in the studies of amino acid profiles in sarcopenia and ...systematically presented the clinical significance of amino acid flux in sarcopenia.
We systematically searched in MEDLINE, EMBASE, and Cochrane library from inception to June 1, 2021 to capture all studies examining metabolomics of sarcopenia. We used the following keywords: sarcopenia, metabonomics, metabolomics, amino acid profile, and mass spectrometry. Original articles comparing amino acid patterns between persons with and without sarcopenia were included. Two independent investigators independently completed title and abstract screening, data extraction, and quality evaluation. We used a random effects model to examine the association between amino acids levels and sarcopenia. Sensitivity analyses restricted the analyses to studies in which muscle mass was measured by bioelectrical impedance analysis. Study quality was evaluated according to the Agency for Healthcare Research and Quality (AHRQ) checklist.
The systematic research yielded six eligible articles, comprising 1,120 participants. Five studies used muscle mass in combination with physical performance and/or muscle strength as the criteria to diagnose sarcopenia, while one study used muscle mass as a diagnostic criterion alone. We found that the concentrations of branched-chain amino acids leucine (standardized mean difference SMD -1.249; 95% confidence interval CI: -2.275, -0.223,
= 0.02, I
= 97.7%), isoleucine (SMD -1.077; 95% CI: -2.106, -0.049,
= 0.04, I
= 97.8%), and aromatic amino acid tryptophan (SMD -0.923; 95% CI: -1.580, -0.265,
= 0.01, I
= 89.9%) were significantly reduced in individuals with sarcopenia. Study results were robust in sensitivity analysis.
The homeostasis of amino acids is critical to maintaining muscle health. The profiles of amino acids might be useful biomarkers for the characterization of sarcopenia. Future studies are warranted to study the clinical significance of amino acids in the diagnosis and treatment of sarcopenia.
Long non-coding RNAs (lncRNAs) function as critical regulators to participate in tumor progression and metastasis. However, their roles in non-small cell lung cancer (NSCLC) are poorly understood. In ...this study, we found that the expression of the lncRNA linc00460 is significantly upregulated in NSCLC tumors and associated with poor prognosis for NSCLC patients, implying that linc00460 is important for lung cancer development. The accurate transcription initiation and termination sites of linc00460 were then identified by rapid-amplification of cDNA ends (RACE) technologies, and the sequencing data demonstrated that linc00460, predominantly located in the cytoplasm of lung cancer cells, is a novel transcript variant. Functional studies through gain- and loss-of-function strategies showed that linc00460 promotes cell migration and invasion through inducing epithelial-mesenchymal transition in lung cancer cells, whereas it has no effect on cell proliferation. The mechanism investigations through RNA pull-down assay and mass spectrometry identified that hnRNP K physically interacts with linc00460, and it also participates in cell migration and invasion. Therefore, our findings suggest that linc00460 acts as an oncogene in NSCLC to promote cell migration and highlight the potential prognostic and therapeutic values of linc00460 for NSCLC patients.
•Upregulation of the lncRNA linc00460 expression in NSCLC tumors.•Linc00460 promotes cell migration and invasion through inducing EMT in lung cancer cells.•hnRNP K physically interacts with linc00460 and participate in cell migration.
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