Defensin
Defensins are small cysteine-rich cationic proteins across cellular life, including vertebrate and invertebrate animals, plants, and fungi. They are host defense peptides, with members displaying either direct antimicrobial activity, immune signalling activities, or both. They are variously active against bacteria, fungi and many enveloped and nonenveloped viruses. They are typically 18-45 amino acids in length, with three or four highly conserved disulphide bonds.
In animals, they are produced by cells of the innate immune system and epithelial cells, whereas in plants and fungi they are produced by a wide variety of tissues. An organism usually produces many different defensins, some of which are stored inside the cells, and others are secreted into the extracellular medium. For those that directly kill microbes, their mechanism of action varies from disruption of the microbial cell membrane to metabolic disruption.
Varieties
The name 'defensin' was coined in the mid 1980s, though the proteins have been variously called 'Cationic Antimicrobial Proteins', 'Neutrophil peptides', 'Gamma thionins' amongst others.Proteins called 'defensins' are not all evolutionarily related to one another. In stead fall into two broad superfamilies, each of which contains multiple families. One superfamily, the trans-defensins, contains the defensins found in humans and other vertebrates as well as some invertebrates. The other superfamily, cis-defensins, contains the defensins found in invertebrates, plants and fungi. The superfamilies and families are determined overall tertiary structure and each family usually has a conserved pattern of disulphide bonds. All defensins form small and compact folded structures, typically with a high positive charge that are highly stable due to the multiple disulphide bonds. In all families, the underlying genes responsible for defensin production are highly polymorphic.
Trans defensins
Vertebrate defensins
All vertebrates have both α-defensins and the β-defensins. Some primates additionally have the much smaller θ-defensins. In general, both α- and β-defensins are encoded by two-exon genes, where the first exon encodes for a hydrophobic leader sequence and the cysteine-rich sequence. The disulfide linkages formed by the cysteines have been suggested to be essential for activities related to innate immunity in mammals, but are not necessarily required for antimicrobial activity. Theta defensins form a single beta hairpin structure and therefore also represent a distinct group. Only alpha and beta defensins are expressed in humans.Cis-defensins
Invertebrate defensins
Most defensin found in invertebrate animals are distinct from those found in vertebrates. The most well-studied of these are arthropod defensins, and mollusc defensins.Plant defensins
Fungal defensins
Bacterial defensins
Related proteins
In addition to the defensins involved in host defence, there are a number of related Defensin-Like Peptides that have evolved to have other activities.Toxins
There appear to have been multiple evolutionary recruitments of defensins to be toxin proteins used in the venoms of animals. and act via a completely different mechanism to their antimicrobial relatives, binding directly to ion channels to disrupting nerve signals. Examples include the crotamine toxin in snake venom, many scorpion toxins, some sea anemone toxins, and one of the toxins in platypus venom. Indeed, an insect defensin has been experimentatlly converted into a toxin by deletion of a small loop that otherwise sterically hindered interactions with the ion channels.Signalling
In vertebrates, some α- and β-defensins are involved in signalling between the innate immune and adaptive immune systems. In plants, a specialised family of DLPs is involved in signalling to detect if self-pollination has occurred and induce self-incompatibility to prevent inbreeding.Enzyme inhibitors
Some antimicrobial defensins also have enzyme inhibitory activity, and some DLPs function primarily as enzyme inhibitors, acting as antifeedants.Function
In immature marsupials, because their immune system is underdeveloped at the time of birth, defensins play a major role in defense against pathogens. They are produced in the milk of the mother as well as by the young marsupial in question.In human breast milk, defensins play a central role in neonate immunity.
The human genome contains theta-defensin genes, but they have a premature stop codon, hampering their expression. An artificial human theta-defensin, retrocyclin, was created by 'fixing' the pseudogene, and it was shown to be effective against HIV and other viruses, including herpes simplex virus and influenza A. They act primarily by preventing these viruses from entering their target cells.
Also interesting is the effect of alpha-defensins on the exotoxin produced by anthrax. Chun Kim et al. showed how anthrax, which produces a metalloprotease lethal factor protein to target MAPKK, is vulnerable to human neutrophil protein-1. This group showed HNP-1 to behave as a reversible noncompetitive inhibitor of LF.
They have generally been considered to contribute to mucosal health; however, it is possible that these peptides can be considered biological factors that can be upregulated by bioactive compounds present in human breast milk. In this sense, the intestinal production of antimicrobial peptides as hBD2 and hBD4 by trefoil from milk might play an important role on neonate colonization, thereby enhancing the immune response of newborns against pathogens with which they may come in contact.
Pathology
The alpha defensin peptides are increased in chronic inflammatory conditions.Alpha defensin are increased in several cancers, including colorectal cancer.
An imbalance of defensins in the skin may contribute to acne.
A reduction of ileal defensins may predispose to Crohn's disease.
In one small study, a significant increase in alpha defensin levels was detected in T cell lysates of schizophrenia patients; in discordant twin pairs, unaffected twins also had an increase, although not as high as that of their ill siblings. The authors suggested that alpha-defensin levels might prove a useful marker for schizophrenia risk.
Defensins are found in the human skin during inflammatory conditions like psoriasis and also during wound healing.