Candidalysin
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Candidalysin is a cytolytic 31-
amino acid Amino acids are organic compounds that contain both amino and carboxylic acid functional groups. Although hundreds of amino acids exist in nature, by far the most important are the alpha-amino acids, which comprise proteins. Only 22 alpha a ...
α-helical
amphipathic An amphiphile (from the Greek αμφις amphis, both, and φιλíα philia, love, friendship), or amphipath, is a chemical compound possessing both hydrophilic (''water-loving'', polar) and lipophilic (''fat-loving'') properties. Such a compoun ...
peptide Peptides (, ) are short chains of amino acids linked by peptide bonds. Long chains of amino acids are called proteins. Chains of fewer than twenty amino acids are called oligopeptides, and include dipeptides, tripeptides, and tetrapeptides. ...
toxin A toxin is a naturally occurring organic poison produced by metabolic activities of living cells or organisms. Toxins occur especially as a protein or conjugated protein. The term toxin was first used by organic chemist Ludwig Brieger (1849 ...
secreted by the opportunistic pathogen ''
Candida albicans ''Candida albicans'' is an opportunistic pathogenic yeast that is a common member of the human gut flora. It can also survive outside the human body. It is detected in the gastrointestinal tract and mouth in 40–60% of healthy adults. It is usu ...
''. This toxin is a fungal example of a classical
virulence factor Virulence factors (preferably known as pathogenicity factors or effectors in plant science) are cellular structures, molecules and regulatory systems that enable microbial pathogens (bacteria, viruses, fungi, and protozoa) to achieve the following ...
. Hyphal morphogenesis in ''C. albicans'' is associated with damage to host
epithelial cells Epithelium or epithelial tissue is one of the four basic types of animal tissue, along with connective tissue, muscle tissue and nervous tissue. It is a thin, continuous, protective layer of compactly packed cells with a little intercell ...
; during this process Candidalysin is released and intercalates in host membranes. Candidalysin promotes damage of oral epithelial cells and induces lactate dehydrogenase release and calcium ion influx. It is unique in the fact that it is the first peptide toxin to be identified in any human fungal pathogen. Candidalysin is a product of the larger protein Ece1 (extent of cell elongation 1). Sequential processing of Ece1 at lysine/arginine residues by the proteases Kex2 and Kex1 releases several peptides, including the toxin Candidalysin. Consequently, Candidalysin is also known as Ece1-III62–92K. ''C. albicans s''trains missing Candidalysin do not damage epithelial cells and are said to be avirulent with respect to mucosal infections. The toxin is also responsible for the activation and propagation of a cellular immune response.


Epithelial damage

During epithelial infection, as candidalysin levels accumulate, tissue damage occurs. Candidalysin promotes damage of oral epithelial cells, which can be measured by the release of lactate dehydrogenase, and calcium ion influx which are characteristics of membrane destabilization and cell damage. Candidalysin is able to cause epithelial damage through membrane intercalation and permeabilization. It causes IL-1β release and is a driver of inflammasome activation in macrophages.


Immune response

Epithelial immunity can recognize Ece1-III62–92K without harming cells. Epithelial cells have evolved to particularly recognize the peptide, which indicates that during mucosal infection the fungus secretes this toxin. Immune cells can either be exposed extracellularly or intracellularly and this is due to the fact that phagocytes can be exposed to the fungal hyphae pre-phagocytosis or post-phagocytosis. Epithelial immunity is achieved predominantly through mitogen-activated protein kinase (
MAPK A mitogen-activated protein kinase (MAPK or MAP kinase) is a type of protein kinase that is specific to the amino acids serine and threonine (i.e., a serine/threonine-specific protein kinase). MAPKs are involved in directing cellular responses to ...
) signaling, more specifically the p38 pathway. The p38 pathway leads to the activation of AP-1 transcription factor c-Fos and the ERK1/2 pathway. The ERK1/2 pathway then leads to the activation of the enzyme MAPK phosphatase 1 which regulates the immune response.


p38 MAPK pathway

The p38 mitogen activated protein kinase (MAPK) pathway is similar to the
JNK c-Jun N-terminal kinases (JNKs), were originally identified as kinases that bind and phosphorylate c-Jun on Ser-63 and Ser-73 within its transcriptional activation domain. They belong to the mitogen-activated protein kinase family, and ar ...
pathway but differs from the ERK pathway. The p38 MAP kinase, JNK MAP kinase, and ERK MAP kinase are all types of mammalian MAP kinases. The p38 MAP kinase is activated by two other MAP kinases known as MKK3 and MKK4. MKK4 is also known to activate the JNK MAP kinase, however, MKK3 is unique to the p38 MAP kinase. The p38 MAPK pathway is required to be activated by dual phosphorylation of the amino acids: tyrosine and threonine and also environmental stress and pro-inflammatory cytokines. Examples of environmental stress than can activate the p38 MAP Kinase include UV radiation and osmotic stress. Examples of pro-inflammatory cytokines that can activate the p38 MAP Kinase include tumor necrosis factor, Interleukin-1, and lipopolysaccharide (LPS). The p38 MAP kinase plays an important role in regulating Interleukin-10 synthesis and
toll-like receptor Toll-like receptors (TLRs) are a class of proteins that play a key role in the innate immune system. They are single-pass membrane-spanning receptors usually expressed on sentinel cells such as macrophages and dendritic cells, that recognize ...
signaling.


MAPK phosphatase MKP1

MAPK Phosphatase 1 negatively regulates the activity of mitogen activate protein kinase (MAPK) activity. A deficiency of this phosphatase leads to a prolonged and continual activation of the p38 MAP kinase and JNK MAP kinase. MAPK phosphatase 1 is the founding member of the family of MAPK phosphatases which is a group of 11 phosphatases. The N-terminus of MAPK phosphatase 1 is responsible for the localization of the nucleus. The p38 MAPK and JNK pathways are preferred to be dephosphorylated over the ERK pathway.


References

{{Reflist, 30em Candida (fungus) Mycotoxins