Individual Impact of Distinct Polysialic Acid Chain Lengths on the Cytotoxicity of Histone H1, H2A, H2B, H3 and H4.

Kristina Zlatina,Sebastian Galuska,Thomas Lütteke

doi:10.3390/polym9120720

Kristina Zlatina, Sebastian Galuska + Show 1 more

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https://doi.org/10.3390/polym9120720

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Abstract

Neutrophils are able to neutralize pathogens by phagocytosis, by the release of antimicrobial components, as well as by the formation of neutrophil extracellular traps (NETs). The latter possibility is a DNA-meshwork mainly consisting of highly concentrated extracellular histones, which are not only toxic for pathogens, but also for endogenous cells triggering several diseases. To reduce the negative outcomes initiated by extracellular histones, different approaches like antibodies against histones, proteases, and the polysaccharide polysialic acid (polySia) were discussed. We examined whether each of the individual histones is a binding partner of polySia, and analyzed their respective cytotoxicity in the presence of this linear homopolymer. Interestingly, all of the histones (H1, H2A, H2B, H3, and H4) seem to interact with α2,8-linked sialic acids. However, we observed strong differences regarding the required chain length of polySia to bind histone H1, H2A, H2B, H3, and H4. Moreover, distinct degrees of polymerization were necessary to act as a cytoprotective agent in the presence of the individual histones. In sum, the outlined results described polySia-based strategies to bind and/or to reduce the cytotoxicity of individual histones using distinct polySia chain length settings.

Highlights

IntroductionNeutrophil extracellular traps (NETs) serve to combat pathogens, such as fungi, viruses, and bacteria
Besides other mechanisms, neutrophil extracellular traps (NETs) serve to combat pathogens, such as fungi, viruses, and bacteria
In a previous study [32], we already used a model of a histone-DNA-complex (Protein Data Bank entry 3wa9) and four polysialic acid (polySia) chains with a chain length of 20 sialic acid units to get a hint for possible binding areas between polySia and histone octamers

Summary

Introduction

Neutrophil extracellular traps (NETs) serve to combat pathogens, such as fungi, viruses, and bacteria. For this purpose, NETs are a meshwork of antimicrobial peptides (AMP), chromatin, and enzymes [1]. The linker histone H1, as well as the four core subunits H2A, H2B, H3, and H4 possess—like other AMPs—a positive charge and are able to bind and penetrate negatively charged cell membranes [4,5]. This ability is toxic for invaders, and for host cells [6]. Urban and coworkers demonstrated that histones are the most abundant proteins in NETs and the concentration is significantly higher for H2A (26.29%) and H2B (23.95%), representing approximately

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