Pepsin-Mediated Processing of the Cytoplasmic Histone H2A to Strong Antimicrobial Peptide Buforin I

Kim, Hun Sik; Yoon, Hyun-Joong; Minn, Il; Park, Chan Bae; Lee, Won Taek; Zasloff, Michael; Kim, Sun Chang

doi:10.4049/jimmunol.165.6.3268

Cited by 110 publications

(100 citation statements)

References 46 publications

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“…Some of these acetylation sites were previously found in shrimp histones (Ouvry-Patat and Schey, 2007). The histones previously examined for antimicrobial activity are reported to be un-acetylated (Kim et al, 2000), though there was no indication of whether acetylation affected antimicrobial efficacy. Second, we compared the antibacterial potencies of droplet-derived histones with commercial calf thymus histones isolated from a calf thymus nuclear fraction in both bactericidal (killing bacteria outright) and bacteriostatic (inhibiting the growth or reproduction of bacteria) activity assays.…”

Section: Resultsmentioning

confidence: 99%

A novel role for lipid droplets in the organismal antibacterial response

Anand

Cermelli

et al. 2012

eLife

109

132

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We previously discovered histones bound to cytosolic lipid droplets (LDs); here we show that this forms a cellular antibacterial defense system. Sequestered on droplets under normal conditions, in the presence of bacterial lipopolysaccharide (LPS) or lipoteichoic acid (LTA), histones are released from the droplets and kill bacteria efficiently in vitro. Droplet-bound histones also function in vivo: when injected into Drosophila embryos lacking droplet-bound histones, bacteria grow rapidly. In contrast, bacteria injected into embryos with droplet-bound histones die. Embryos with droplet-bound histones displayed more than a fourfold survival advantage when challenged with four different bacterial species. Our data suggests that this intracellular antibacterial defense system may function in adult flies, and also potentially in mice.DOI: http://dx.doi.org/10.7554/eLife.00003.001

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Section: Resultsmentioning

confidence: 99%

A novel role for lipid droplets in the organismal antibacterial response

Anand

Cermelli

et al. 2012

eLife

109

132

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“…Recently, the presence of histones in both the cytoplasm and nucleus has been reported (24,53,54,68,69), and the secretion of histone proteins into the extracellular milieu was also observed (24, 70 -72). It is becoming clear that histone proteins are present in both the cytoplasm and the nucleus of rapidly regenerating or transcriptionally active cells such as placental, gastrointestinal (24,54), and skin (73,74) epithelial cells.…”

Section: Discussionmentioning

confidence: 99%

“…Given that a heparin-binding lectin from human placenta was hypothesized to be histone H2B (51) and that a neuronal LPS-binding protein was identified as histone H1 (52), we were prompted to investigate the LPS binding and neutralization abilities of histones H2A and H2B. To date, the majority of studies on host defense involving histone proteins have been focused on broad-spectrum antimicrobial activities (24,53,54). The interaction of histone proteins with LPS and the influence of the O-Ag, core, or lipid A domains of LPS on LPS binding to histones had heretofore not been evaluated.…”

Section: Discussionmentioning

confidence: 99%

“…It is becoming clear that histone proteins are present in both the cytoplasm and the nucleus of rapidly regenerating or transcriptionally active cells such as placental, gastrointestinal (24,54), and skin (73,74) epithelial cells. Indeed, we detected nuclear staining of some syncytiotrophoblasts and amnion epithelial cells with anti-phospho-histone H3 Ab, a mitosis marker (data not shown).…”

Section: Discussionmentioning

confidence: 99%

“…In contrast to highly specific adaptive immunity, which is not triggered rapidly enough to protect against exposure to pathogens, the innate immune system provides a rapid and nonspecific response, and thereby contributes to the first line of defense against infection. The recent discovery of antimicrobial proteins within the human respiratory epithelium (22,23), the gastrointestinal epithelium (24,25), Paneth cells of the small intestine (26,27), and the urogenital epithelium (28) has prompted us to examine placental tissue and associated membranes for similar agents. From the fetal membrane of human placenta, we have isolated two salt-resistant proteins with antimicrobial and endotoxin-neutralizing activities.…”

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confidence: 99%

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Endotoxin-Neutralizing Antimicrobial Proteins of the Human Placenta

Kim

Cho

Park

et al. 2002

The Journal of Immunology

Self Cite

118

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Microbial colonization and infection of placental tissues often lead to adverse pregnancy outcomes such as preterm birth, a leading cause of neonatal morbidity and mortality. The fetal membranes of the placenta, a physical and active barrier to microbial invasion, encapsulate the fetus and secure its intrauterine environment. To examine the innate defense system of the human placenta, antimicrobial peptides were isolated from the fetal membranes of human placenta and characterized biochemically. Two salt-resistant antimicrobial host proteins were purified to homogeneity using heparin-affinity and reversed-phase HPLC. Characterization of these proteins revealed that they are identical to histones H2A and H2B. Histones H2A and H2B showed dose-dependent inhibition of the endotoxin activity of LPS and inhibited this activity by binding to and therefore blocking both the core and lipid A moieties of LPS. Consistent with a role for histones in the establishment of placental innate defense, histones H2A and H2B were highly expressed in the cytoplasm of syncytiotrophoblasts and amnion cells, where the histone proteins were localized mainly to the epithelial surface. Furthermore, culturing of amnion-derived WISH cells led to the constitutive release of histone H2B, and histones H2A and H2B contribute to bactericidal activity of amniotic fluid. Our studies suggest that histones H2A and H2B may endow the epithelium of the placenta with an antimicrobial and endotoxin-neutralizing barrier against microorganisms that invade this immune-privileged site.

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Advances in antimicrobial peptide immunobiology

et al. 2006

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Antimicrobial peptides are ancient components of the innate immune system and have been isolated from organisms spanning the phylogenetic spectrum. Over an evolutionary time span, these peptides have retained potency, in the face of highly mutable target microorganisms. This fact suggests important coevolutionary influences in the host-pathogen relationship. Despite their diverse origins, the majority of antimicrobial peptides have common biophysical parameters that are likely essential for activity, including small size, cationicity, and amphipathicity. Although more than 900 different antimicrobial peptides have been characterized, most can be grouped as belonging to one of three structural classes: (1) linear, often of alpha-helical propensity; (2) cysteine stabilized, most commonly conforming to beta-sheet structure; and (3) those with one or more predominant amino acid residues, but variable in structure. Interestingly, these biophysical and structural features are retained in ribosomally as well as nonribosomally synthesized peptides. Therefore, it appears that a relatively limited set of physicochemical features is required for antimicrobial peptide efficacy against a broad spectrum of microbial pathogens. During the past several years, a number of themes have emerged within the field of antimicrobial peptide immunobiology. One developing area expands upon known microbicidal mechanisms of antimicrobial peptides to include targets beyond the plasma membrane. Examples include antimicrobial peptide activity involving structures such as extracellular polysaccharide and cell wall components, as well as the identification of an increasing number of intracellular targets. Additional areas of interest include an expanding recognition of antimicrobial peptide multifunctionality, and the identification of large antimicrobial proteins, and antimicrobial peptide or protein fragments derived thereof. The following discussion highlights such recent developments in antimicrobial peptide immunobiology, with an emphasis on the biophysical aspects of host-defense polypeptide action and mechanisms of microbial resistance.

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Pepsin-Mediated Processing of the Cytoplasmic Histone H2A to Strong Antimicrobial Peptide Buforin I

Cited by 110 publications

References 46 publications

A novel role for lipid droplets in the organismal antibacterial response

A novel role for lipid droplets in the organismal antibacterial response

Endotoxin-Neutralizing Antimicrobial Proteins of the Human Placenta

Advances in antimicrobial peptide immunobiology

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