Biology:Cathelicidin

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Short description: Group of antimicrobial peptides in vertebrates


A representation of the 3D structure of the protein myoglobin showing turquoise α-helices.
Generic protein structure example

Cathelicidin antimicrobial peptide (CAMP) is a polypeptide that is primarily stored in the lysosomes of macrophages and polymorphonuclear leukocytes (PMNs); in humans, the CAMP gene encodes the peptide precursor CAP-18 (18 kDa), which is processed by proteinase 3-mediated extracellular cleavage into the active form LL-37.[1][2] LL-37 is the only peptide in the Cathelicidin family found in the human body.[3]

Cathelicidin peptides are dual-natured molecules called amphiphiles: one end of the molecule is attracted to water and repelled by fats and proteins, and the other end is attracted to fat and proteins and repelled by water. Members of this family react to pathogens by disintegrating, damaging, or puncturing cell membranes.

Cathelicidins thus serve a critical role in mammalian innate immune defense against invasive bacterial infection.[4] The cathelicidin family of peptides are classified as antimicrobial peptides (AMPs). The AMP family also includes the defensins. Whilst the defensins share common structural features, cathelicidin-related peptides are highly heterogeneous.[4] Members of the cathelicidin family of antimicrobial polypeptides are characterized by a highly conserved region (cathelin domain) and a highly variable cathelicidin peptide domain.[4]

Cathelicidin peptides have been isolated from many different species of mammals. Cathelicidins are mostly found in neutrophils, monocytes, mast cells, dendritic cells and macrophages[5] after activation by bacteria, viruses, fungi, parasites or the hormone 1,25-D, which is the hormonally active form of vitamin D.[6] They have been found in some other cells, including epithelial cells and human keratinocytes.[7]

Etymology

The term was coined in 1995 from cathelin, due to the characteristic cathelin-like domain present in cathelicidins.[8] The name cathelin itself is coined from cathepsin L inhibitor in 1989.[9]

Mechanism of antimicrobial activity

The general rule of the mechanism triggering cathelicidin action, like that of other antimicrobial peptides, involves the disintegration (damaging and puncturing) of cell membranes of organisms toward which the peptide is active.[10] Antimicrobial effects have been observed against fungal, bacterial, and viral pathogens.[citation needed]

Cathelicidins rapidly destroy the lipoprotein membranes of microbes enveloped in phagosomes after fusion with lysosomes in macrophages. Therefore, LL-37 can inhibit the formation of bacterial biofilms.[11]

The pleiotropic properties of LL-37 in relation to the different cells and tissues

Other activities

LL-37 plays a role in the activation of cell proliferation and migration, contributing to the wound closure process.[12] All these mechanisms together play an essential role in tissue homeostasis and regenerative processes. Moreover, it has an agonistic effect on various pleiotropic receptors, for example, formyl peptide receptor like-1 (FPRL-1),[13] purinergic receptor P2X7, epidermal growth factor receptor (EGFR)[14] or insulin-like growth factor-1 receptor (IGF-1R).[15] These receptors play an important immunomodulatory role in, among other things, anti-tumor immune response.[citation needed]

Furthermore, it induces angiogenesis[16] and regulates apoptosis.[17] These processes are dysregulated during tumor development, and thus LL-37 might be involved in pathogenesis of malignant tumors.[citation needed]

Characteristics

Cathelicidins range in size from 12 to 80 amino acid residues and have a wide range of structures.[18] Most cathelicidins are linear peptides with 23-37 amino acid residues, and fold into amphipathic α-helices. Additionally cathelicidins may also be small-sized molecules (12-18 residues) with beta-hairpin structures, stabilized by one or two disulphide bonds. Even larger cathelicidin peptides (39-80 amino acid residues) are also present. These larger cathelicidins display repetitive proline motifs forming extended polyproline-type structures.[4]

In 1995, Gudmundsson et al. assumed that the active antimicrobial peptide is formed of a 39-residue C-terminal domain (termed FALL-39). However, only a year later stated that the matured AMP, now called LL-37, is in reality two amino acids shorter than FALL-39.[19][20]

The cathelicidin family shares primary sequence homology with the cystatin[21] family of cysteine proteinase inhibitors, although amino acid residues thought to be important in such protease inhibition are usually lacking.

Non-human orthologs

Cathelicidin peptides have been found in humans, monkeys, mice, rats, rabbits, guinea pigs, pandas, pigs, cattle, frogs, sheep, goats, chickens, and horses. Antibodies to the human LL-37/hCAP-18 have been used to find cathelicidin-like compounds in a marsupial.[22] About 30 cathelicidin family members have been described in mammals.[citation needed]

Currently identified cathelicidin peptides include the following:[4]

  • Human: hCAP-18 (cleaved into LL-37)
  • Rhesus monkey: RL-37
  • Mice:CRAMP-1/2, (Cathelicidin-related Antimicrobial Peptide[23]
  • Rats: rCRAMP
  • Rabbits: CAP-18
  • Guinea pig: CAP-11
  • Pigs: PR-39, Prophenin, PMAP-23,36,37
  • Cattle: BMAP-27,28,34 (Bovine Myeloid Antimicrobial Peptides); Bac5, Bac7
  • Frogs: cathelicidin-AL (found in Amolops loloensis)[24]
  • Chickens: Four cathelicidins, fowlicidins 1,2,3 and cathelicidin Beta-1 [25]
  • Tasmanian Devil: Saha-CATH5 [26]
  • Salmonids: CATH1 and CATH2


Clinical significance

Patients with rosacea have elevated levels of cathelicidin and elevated levels of stratum corneum tryptic enzymes (SCTEs). Cathelicidin is cleaved into the antimicrobial peptide LL-37 by both kallikrein 5 and kallikrein 7 serine proteases. Excessive production of LL-37 is suspected to be a contributing cause in all subtypes of Rosacea.[27] Antibiotics have been used in the past to treat rosacea, but antibiotics may only work because they inhibit some SCTEs.[28]

Lower plasma levels of human cathelicidin antimicrobial protein (hCAP18) appear to significantly increase the risk of death from infection in dialysis patients.[29] The production of cathelicidin is up-regulated by vitamin D.[30][31]

SAAP-148 (a synthetic antimicrobial and antibiofilm peptide) is a modified version of LL-37 that has enhanced antimicrobial activities compared to LL-37. In particular, SAAP-148 was more efficient in killing bacteria under physiological conditions.[32] In addition, SAAP-148 synergises with the repurposed antibiotic halicin against antibiotic-resistant bacteria and biofilms.[33]

LL-37 is thought to play a role in psoriasis pathogenesis (along with other anti-microbial peptides). In psoriasis, damaged keratinocytes release LL-37 which forms complexes with self-genetic material (DNA or RNA) from other cells. These complexes stimulate dendritic cells (a type of antigen presenting cell) which then release interferon α and β which contributes to differentiation of T-cells and continued inflammation.[34] LL-37 has also been found to be a common auto-antigen in psoriasis; T-cells specific to LL-37 were found in the blood and skin in two thirds of patients with moderate to severe psoriasis.[34]

LL-37 binds to the peptide Ab, which is associated with Alzheimer's disease. An imbalance between LL-37 and Ab may be a factor affecting AD-associated fibrils and plaques. Chronic, oral Porphyromonas gingivalis, and herpesvirus (HSV-1) infections may contribute to the progression of Alzheimer's dementia.[35][36]

Applications

Research into the AMP family—particularly in regards to their mechanism of action—has been ongoing for nearly 20 years. Despite sustained interest, treatments derived or utilizing AMPs have not been widely adopted for clinical use for several reasons.[37] One, drug candidates from AMPs have a narrow window of bioavailability, because peptides are quickly broken down by proteases. Two, peptide drugs are more expensive than small molecule drugs to produce, which is problematic since peptide drugs must be given in large doses to counter rapid enzymatic breakdown. These qualities also limit routes of administration, typically to injection, infusion, or slow release therapy.[38]

See also

References

  1. ↑ "Entrez Gene: CAMP cathelicidin antimicrobial peptide". https://www.ncbi.nlm.nih.gov/sites/entrez?Db=gene&Cmd=ShowDetailView&TermToSearch=820. 
  2. ↑ UniProt entry: P49913 Retrieved 29 November 2019
  3. ↑ "LL-37, the only human member of the cathelicidin family of antimicrobial peptides". Biochimica et Biophysica Acta (BBA) - Biomembranes 1758 (9): 1408–1425. September 2006. doi:10.1016/j.bbamem.2006.03.030. PMID 16716248. 
  4. ↑ 4.0 4.1 4.2 4.3 4.4 "Cathelicidins, multifunctional peptides of the innate immunity". Journal of Leukocyte Biology 75 (1): 39–48. January 2004. doi:10.1189/jlb.0403147. PMID 12960280. 
  5. ↑ "A comprehensive summary of LL-37, the factotum human cathelicidin peptide". Cellular Immunology 280 (1): 22–35. November 2012. doi:10.1016/j.cellimm.2012.11.009. PMID 23246832. 
  6. ↑ "Toll-like receptor triggering of a vitamin D-mediated human antimicrobial response". Science 311 (5768): 1770–3. March 2006. doi:10.1126/science.1123933. PMID 16497887. Bibcode: 2006Sci...311.1770L. 
  7. ↑ "The peptide antibiotic LL-37/hCAP-18 is expressed in epithelia of the human lung where it has broad antimicrobial activity at the airway surface". Proceedings of the National Academy of Sciences of the United States of America 95 (16): 9541–6. August 1998. doi:10.1073/pnas.95.16.9541. PMID 9689116. Bibcode: 1998PNAS...95.9541B. 
  8. ↑ "Cathelicidins: a novel protein family with a common proregion and a variable C-terminal antimicrobial domain". FEBS Letters 374 (1): 1–5. October 1995. doi:10.1016/0014-5793(95)01050-o. PMID 7589491. 
  9. ↑ "Primary structure of a new cysteine proteinase inhibitor from pig leucocytes". FEBS Letters 255 (2): 211–4. September 1989. doi:10.1016/0014-5793(89)81093-2. PMID 2792375. 
  10. ↑ "Cathelicidins: family of antimicrobial peptides. A review". Molecular Biology Reports 39 (12): 10957–70. December 2012. doi:10.1007/s11033-012-1997-x. PMID 23065264. 
  11. ↑ "Inhibition and destruction of Pseudomonas aeruginosa biofilms by antibiotics and antimicrobial peptides". Peptides 62: 32–7. December 2014. doi:10.1016/j.peptides.2014.09.021. PMID 25285879. 
  12. ↑ "Human endogenous antibiotic LL-37 stimulates airway epithelial cell proliferation and wound closure". American Journal of Physiology. Lung Cellular and Molecular Physiology 289 (5): L842-8. November 2005. doi:10.1152/ajplung.00286.2004. PMID 15964896. 
  13. ↑ "LL-37, the neutrophil granule- and epithelial cell-derived cathelicidin, utilizes formyl peptide receptor-like 1 (FPRL1) as a receptor to chemoattract human peripheral blood neutrophils, monocytes, and T cells". The Journal of Experimental Medicine 192 (7): 1069–74. October 2000. doi:10.1084/jem.192.7.1069. PMID 11015447. 
  14. ↑ "The host defence peptide LL-37/hCAP-18 is a growth factor for lung cancer cells". Lung Cancer 59 (1): 12–23. January 2008. doi:10.1016/j.lungcan.2007.07.014. PMID 17764778. 
  15. ↑ "Identification of the cathelicidin peptide LL-37 as agonist for the type I insulin-like growth factor receptor". Oncogene 31 (3): 352–65. January 2012. doi:10.1038/onc.2011.239. PMID 21685939. 
  16. ↑ "An angiogenic role for the human peptide antibiotic LL-37/hCAP-18". The Journal of Clinical Investigation 111 (11): 1665–72. June 2003. doi:10.1172/JCI17545. PMID 12782669. 
  17. ↑ "FK-16 derived from the anticancer peptide LL-37 induces caspase-independent apoptosis and autophagic cell death in colon cancer cells". PLOS ONE 8 (5): e63641. 2013-05-20. doi:10.1371/journal.pone.0063641. PMID 23700428. Bibcode: 2013PLoSO...863641R. 
  18. ↑ "Structural features and biological activities of the cathelicidin-derived antimicrobial peptides". Biopolymers 55 (1): 31–49. 2000. doi:10.1002/1097-0282(2000)55:1<31::AID-BIP40>3.0.CO;2-9. PMID 10931440. 
  19. ↑ "FALL-39, a putative human peptide antibiotic, is cysteine-free and expressed in bone marrow and testis". Proceedings of the National Academy of Sciences of the United States of America 92 (1): 195–9. January 1995. doi:10.1073/pnas.92.1.195. PMID 7529412. Bibcode: 1995PNAS...92..195A. 
  20. ↑ "The human gene FALL39 and processing of the cathelin precursor to the antibacterial peptide LL-37 in granulocytes". European Journal of Biochemistry 238 (2): 325–32. June 1996. doi:10.1111/j.1432-1033.1996.0325z.x. PMID 8681941. 
  21. ↑ "Antimicrobial and protease inhibitory functions of the human cathelicidin (hCAP18/LL-37) prosequence". The Journal of Investigative Dermatology 120 (5): 810–6. May 2003. doi:10.1046/j.1523-1747.2003.12132.x. PMID 12713586. 
  22. ↑ "Immunohistochemistry using antibodies to the cathelicidin LL37/hCAP18 in the tammar wallaby, Macropus eugenii". Tissue & Cell 40 (6): 459–466. December 2008. doi:10.1016/j.tice.2008.05.002. PMID 18597803. 
  23. ↑ "Identification of CRAMP, a cathelin-related antimicrobial peptide expressed in the embryonic and adult mouse". The Journal of Biological Chemistry 272 (20): 13088–93. May 1997. doi:10.1074/jbc.272.20.13088. PMID 9148921. 
  24. ↑ "Amphibian cathelicidin fills the evolutionary gap of cathelicidin in vertebrate". Amino Acids 43 (2): 677–85. August 2012. doi:10.1007/s00726-011-1116-7. PMID 22009138. 
  25. ↑ "Tissue expression and developmental regulation of chicken cathelicidin antimicrobial peptides". Journal of Animal Science and Biotechnology 3 (1): 15. May 2012. doi:10.1186/2049-1891-3-15. PMID 22958518. 
  26. ↑ "Cathelicidins in the Tasmanian devil (Sarcophilus harrisii)". Scientific Reports 6: 35019. October 2016. doi:10.1038/srep35019. PMID 27725697. Bibcode: 2016NatSR...635019P. 
  27. ↑ "Cathelicidin LL-37: an antimicrobial peptide with a role in inflammatory skin disease". Annals of Dermatology 24 (2): 126–35. May 2012. doi:10.5021/ad.2012.24.2.126. PMID 22577261. 
  28. ↑ "Increased serine protease activity and cathelicidin promotes skin inflammation in rosacea". Nature Medicine 13 (8): 975–80. August 2007. doi:10.1038/nm1616. PMID 17676051. 
  29. ↑ "Low plasma level of cathelicidin antimicrobial peptide (hCAP18) predicts increased infectious disease mortality in patients undergoing hemodialysis". Clinical Infectious Diseases 48 (4): 418–24. February 2009. doi:10.1086/596314. PMID 19133797. 
  30. ↑ "Antimicrobial peptides of multicellular organisms". Nature 415 (6870): 389–95. January 2002. doi:10.1038/415389a. PMID 11807545. Bibcode: 2002Natur.415..389Z. 
  31. ↑ "Vitamin D and molecular actions on the immune system: modulation of innate and autoimmunity". Journal of Molecular Medicine 88 (5): 441–50. May 2010. doi:10.1007/s00109-010-0590-9. PMID 20119827. 
  32. ↑ "The antimicrobial peptide SAAP-148 combats drug-resistant bacteria and biofilms". Science Translational Medicine 10 (423): eaan4044. January 2018. doi:10.1126/scitranslmed.aan4044. PMID 29321257. 
  33. ↑ "Synergism between the Synthetic Antibacterial and Antibiofilm Peptide (SAAP)-148 and Halicin". Antibiotics 11 (5): 673. May 2022. doi:10.3390/ANTIBIOTICS11050673. PMID 35625317. 
  34. ↑ 34.0 34.1 "Psoriasis Pathogenesis and Treatment". International Journal of Molecular Sciences 20 (6): 1475. March 2019. doi:10.3390/ijms20061475. PMID 30909615. 
  35. ↑ "Porphyromonas gingivalis is a Strong Risk Factor for Alzheimer's Disease". Journal of Alzheimer's Disease Reports 4 (1): 501–511. December 2020. doi:10.3233/ADR-200250. PMID 33532698. 
  36. ↑ "Controversial role of herpesviruses in Alzheimer's disease". PLOS Pathogens 16 (6): e1008575. June 2020. doi:10.1371/journal.ppat.1008575. PMID 32555685. 
  37. ↑ "Biomimetics Research from the Barron Lab". https://web.stanford.edu/group/barronlab/ResearchBioMim.html. 
  38. ↑ "Peptides: New Processes, Lower Costs" (in en-US). 2015-06-30. https://www.genengnews.com/magazine/252/peptides-new-processes-lower-costs/. 

Further reading

External links

  • Overview of all the structural information available in the PDB for UniProt: P49913 (Human Cathelicidin) at the PDBe-KB.



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