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Methylated glycans as conserved targets of animal and fungal innate defense.

ABSTRACT: Effector proteins of innate immune systems recognize specific non-self epitopes. Tectonins are a family of ?-propeller lectins conserved from bacteria to mammals that have been shown to bind bacterial lipopolysaccharide (LPS). We present experimental evidence that two Tectonins of fungal and animal origin have a specificity for O-methylated glycans. We show that Tectonin 2 of the mushroom Laccaria bicolor (Lb-Tec2) agglutinates Gram-negative bacteria and exerts toxicity toward the model nematode Caenorhabditis elegans, suggesting a role in fungal defense against bacteria and nematodes. Biochemical and genetic analysis of these interactions revealed that both bacterial agglutination and nematotoxicity of Lb-Tec2 depend on the recognition of methylated glycans, namely O-methylated mannose and fucose residues, as part of bacterial LPS and nematode cell-surface glycans. In addition, a C. elegans gene, termed samt-1, coding for a candidate membrane transport protein for the presumptive donor substrate of glycan methylation, S-adenosyl-methionine, from the cytoplasm to the Golgi was identified. Intriguingly, limulus lectin L6, a structurally related antibacterial protein of the Japanese horseshoe crab Tachypleus tridentatus, showed properties identical to the mushroom lectin. These results suggest that O-methylated glycans constitute a conserved target of the fungal and animal innate immune system. The broad phylogenetic distribution of O-methylated glycans increases the spectrum of potential antagonists recognized by Tectonins, rendering this conserved protein family a universal defense armor.

SUBMITTER: Wohlschlager T

PROVIDER: S-EPMC4103367 | biostudies-literature | 2014 Jul

REPOSITORIES: biostudies-literature

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Methylated glycans as conserved targets of animal and fungal innate defense.

Wohlschlager Therese T Butschi Alex A Grassi Paola P Sutov Grigorij G Gauss Robert R Hauck Dirk D Schmieder Stefanie S SS Knobel Martin M Titz Alexander A Dell Anne A Haslam Stuart M SM Hengartner Michael O MO Aebi Markus M Künzler Markus M

Proceedings of the National Academy of Sciences of the United States of America 20140530 27

Effector proteins of innate immune systems recognize specific non-self epitopes. Tectonins are a family of β-propeller lectins conserved from bacteria to mammals that have been shown to bind bacterial lipopolysaccharide (LPS). We present experimental evidence that two Tectonins of fungal and animal origin have a specificity for O-methylated glycans. We show that Tectonin 2 of the mushroom Laccaria bicolor (Lb-Tec2) agglutinates Gram-negative bacteria and exerts toxicity toward the model nematode ...[more]

PMID: 24879441

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Project description:UNLABELLED:The purpose of this study was to take advantage of the nematode Caenorhabditis elegans to perform a whole-animal chemical screen to identify potential immune activators that may confer protection against bacterial infections. We identified 45 marketed drugs, out of 1,120 studied compounds, that are capable of activating a conserved p38/PMK-1 mitogen-activated protein kinase pathway required for innate immunity. One of these drugs, the last-resort antibiotic colistin, protected against infections by the Gram-negative pathogens Yersinia pestis and Pseudomonas aeruginosa but not by the Gram-positive pathogens Enterococcus faecalis and Staphylococcus aureus. Protection was independent of the antibacterial activity of colistin, since the drug was administered prophylactically prior to the infections and it was also effective against antibiotic-resistant bacteria. Immune activation by colistin is mediated not only by the p38/PMK-1 pathway but also by the conserved FOXO transcription factor DAF-16 and the transcription factor SKN-1. Furthermore, p38/PMK-1 was found to be required in the intestine for immune activation by colistin. Enhanced p38/PMK-1-mediated immune responses by colistin did not reduce the bacterial burden, indicating that the pathway plays a role in the development of host tolerance to infections by Gram-negative bacteria. IMPORTANCE:The innate immune system represents the front line of our defenses against invading microorganisms. Given the ever-increasing resistance to antibiotics developed by bacterial pathogens, the possibility of boosting immune defenses represents an interesting, complementary approach to conventional antibiotic treatments. Here we report that the antibiotic colistin can protect against infections by a mechanism that is independent of its microbicidal activity. Prophylactic treatment with colistin activates a conserved p38/PMK-1 pathway in the intestine that helps the host better tolerate a bacterial infection. Since p38/PMK-1-mediated immune responses appear to be conserved from plants to mammals, colistin may also activate immunity in higher organisms, including humans. Antibiotics with immunomodulatory properties have the potential of improving the long-term outcome of patients with chronic infectious diseases.

Dataset Information

Methylated glycans as conserved targets of animal and fungal innate defense.

Publications

Methylated glycans as conserved targets of animal and fungal innate defense.

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