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Bacterial Lipoprotein Posttranslational Modifications. New Insights and Opportunities for Antibiotic and Vaccine Development.

ABSTRACT: Lipoproteins are some of the most abundant proteins in bacteria. With a lipid anchor to the cell membrane, they function as enzymes, inhibitors, transporters, structural proteins, and as virulence factors. Lipoproteins activate the innate immune system and have biotechnological applications. The first lipoprotein was described by Braun and Rehn in 1969. Up until recently, however, work on lipoproteins has been sluggish, in part due to the challenges of handling proteins that are anchored to membranes by covalently linked lipids or are membrane integral. Activity in the area has quickened of late. In the past 5 years, high-resolution structures of the membrane enzymes of the canonical lipoprotein synthesis pathway have been determined, new lipoprotein types have been discovered and the enzymes responsible for their synthesis have been characterized biochemically. This has led to a flurry of activity aimed at developing novel antibiotics targeting these enzymes. In addition, surface exposed bacterial lipoproteins have been utilized as candidate vaccine antigens, and their potential to act as self-adjuvanting antigens is increasingly recognized. A summary of the latest developments in lipoproteins and their synthesis, as well as how this information is being exploited for therapeutic purposes is presented here.

SUBMITTER: Smithers L

PROVIDER: S-EPMC8689077 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:BackgroundDue to the unique nature of spermatozoa, which are transcriptionally and translationally silent, the regulation of capacitation is based on the formation of posttranslational modifications of proteins (PTMs). However, the interactions between different types of PTMs during the capacitation remain unclear. Therefore, we aimed to unravel the PTM-based regulation of sperm capacitation by considering the relationship between tyrosine phosphorylation and reversible oxidative PTMs (oxPTMs), i.e., S-nitrosylation and S-glutathionylation. Since reversible oxPTMs may be closely related to peroxyredoxin (PRDX) activity, the second aim was to verify the role of PRDXs in the PTM-based regulation of capacitation.MethodsCryopreserved bull sperm were capacitated in vitro with or without PRDX inhibitor. Qualitative parameters of sperm and symptoms characteristic of capacitation were analyzed. Posttranslational protein modifications (S-nitrosylation, S-glutathionylation, tyrosine phosphorylation) were investigated at the cellular level (flow cytometry, fluorescence microscopy) and at the proteomic level (fluorescent gel-based proteomic approach).ResultsZona-pellucida binding proteins (ACRBP, SPAM1, ZAN, ZPBP1 and IZUMO4) were particularly rich in reversible oxPTMs. Moreover, numerous flagellar proteins were associated with all analyzed types of PTMs, which indicates that the direction of posttranslational modifications was integrated. Inhibition of PRDX activity during capacitation caused an increase in S-nitrosylation and S-glutathionylation and a decrease in tyrosine phosphorylation. Inhibition of PRDXs caused GAPDHS to undergo S-glutathionylation and the GSTO2 and SOD2 enzymes to undergo denitrosylation. Moreover, PRDX inhibition caused the AKAP proteins to be dephosphorylated.ConclusionsOur research provides evidence that crosstalk occurs between tyrosine phosphorylation and reversible oxPTMs during bull sperm capacitation. This study demonstrates that capacitation triggers S-nitrosylation and S-glutathionylation (and reverse reactions) of zona-pellucida binding proteins, which may be a new important mechanism that determines the interaction between sperms and oocytes. Moreover, TCA-related and flagellar proteins, which are particularly rich in PTMs, may play a key role in sperm capacitation. We propose that the deglutathionylation of ODFs and IZUMO4 proteins is a new hallmark of bull sperm capacitation. The obtained results indicate a relationship between PRDX activity and protein phosphorylation, S-glutathionylation and S-nitrosylation. The activity of PRDXs may be crucial for maintaining redox balance and for providing proper PKA-mediated protein phosphorylation during capacitation. Video Abstract.

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Bacterial Lipoprotein Posttranslational Modifications. New Insights and Opportunities for Antibiotic and Vaccine Development.

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