Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) emerge during the last months of 2019, expanding throughout the world as a highly transmissible infectious illness designated as COVID-19. Vaccines have now appeared, but the challenges in producing sufficient material and distributing them around the world means that effective treatments to limit infection and improve recovery are still urgently needed. This review is focused on the relevance of different glycobiological molecules that could potentially serve as or inspire therapeutic tools during SARS-CoV-2 infection. As such, we highlight the glycobiology of the SARS-CoV-2 infection process, where glycans on viral proteins and on host glycosaminoglycans have critical roles in efficient infection. We also take notice of the glycan-binding proteins involved in the infective capacity of virus and in human defense. In addition, we critically evaluate the glycobiological contribution of candidate drugs for COVID-19 therapy such as glycans for vaccines, anti-glycan antibodies, recombinant lectins, lectin inhibitors, glycosidase inhibitors, polysaccharides, and numerous glycosides, emphasizing some opportunities to repurpose FDA-approved drugs. For the next generation drugs suggested here, biotechnological engineering making new probes to block the SARS-CoV-2 infection might be based in the essential glycobiological insight on glycosyltransferases, glycans, glycan-binding proteins and glycosidases related to this pathology.
Biological functions of nuclear proteins are regulated by posttranslational modifications (PTMs) that modulate gene expression and cellular physiology. However, the role of O-linked glycosylation (O-GalNAc) as a PTM of nuclear proteins in the human cell has not been previously reported. Here, we examined in detail the initiation of O-GalNAc glycan biosynthesis, representing a novel PTM of nuclear proteins in the nucleus of human cells, with an emphasis on HeLa cells. Using soluble nuclear fractions from purified nuclei, enzymatic assays, fluorescence microscopy, affinity chromatography, MS, and FRET analyses, we identified all factors required for biosynthesis of O-GalNAc glycans in nuclei: the donor substrate (UDP-GalNAc), nuclear polypeptide GalNAc-transferase activity, and a GalNAc transferase (polypeptide GalNAc-T3). Moreover, we identified O-GalNAc glycosylated proteins in the nucleus and present solid evidence for O-GalNAc glycan synthesis in this organelle. The demonstration of O-GalNAc glycosylation of nuclear proteins in mammalian cells reported here has important implications for cell and chemical biology. The nucleus is one of the most important structures of eukaryotic cells. This complex organelle stores the chromosomes and also regulates their duplication, segregation, repair, and expression through a series of specific processes. The cell's biological information is saved and transferred within the nucleus by three types of biopolymer molecules: DNA, RNA, and proteins (1). Proteins play crucial roles in nuclear scaffolding, DNA assembly, replication, transcription, and transport of molecules. The biological activity of proteins is directly modulated by their conformation, and changes in protein conformation are controlled mainly by post-translational modifications (PTMs). 3 The common PTMs of nuclear proteins are acetyla-This work was supported by CONICET Grant PIP 11220150100226 and SeCyT, UNC Grant 05/C422 (to F. J. I.). The authors declare that they have no conflicts of interest with the contents of this article. This work is dedicated to the memory of Mafalda C. Pellegrini-Irazoqui. This article contains Figs. S1-S5 and Table S1.
Glycosylation is a very frequent post-translational modification in proteins, and the initiation of O-GalNAc glycosylation has been recently described on relevant nuclear proteins. Here we evaluated the nuclear incorporation of a second sugar residue in the biosynthesis pathway of O-GalNAc glycans to yield the terminal core 1 glycan (C1G, Galβ3GalNAcαSer/Thr). Using confocal microscopy, enzymatic assay, affinity chromatography and mass spectrometry, we analyzed intact cells, purified nuclei and soluble nucleoplasms to identify the essential factors for C1G biosynthesis in the cell nucleus. The enzyme C1GalT1 responsible for C1G synthesis was detected inside the nucleus, while catalytic activity of C1Gal-transferase was present in nucleoplasm and purified nuclei. In addition, C1G were detected in the nucleus inside of intact cells, and nuclear proteins exposing C1G were also identified. These evidences represent the first demonstration of core 1 O-GalNAc glycosylation of proteins in the human cell nucleus. These findings reveal a novel post-translational modification on nuclear proteins, with relevant repercussion in epigenetic and chemical biology areas.
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