Defensins (Homo sapiens)

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Bibliography

1. Wang W, Owen SM, Rudolph DL, Cole AM, Hong T, Waring AJ, Lal RB, Lehrer RI.; ''Activity of alpha- and theta-defensins against primary isolates of HIV-1.''; PubMed Europe PMC Scholia
2. Szyk A, Wu Z, Tucker K, Yang D, Lu W, Lubkowski J.; ''Crystal structures of human alpha-defensins HNP4, HD5, and HD6.''; PubMed Europe PMC Scholia
3. Valore EV, Ganz T.; ''Posttranslational processing of defensins in immature human myeloid cells.''; PubMed Europe PMC Scholia
4. Sass V, Schneider T, Wilmes M, Körner C, Tossi A, Novikova N, Shamova O, Sahl HG.; ''Human beta-defensin 3 inhibits cell wall biosynthesis in Staphylococci.''; PubMed Europe PMC Scholia
5. Niyonsaba F, Iwabuchi K, Matsuda H, Ogawa H, Nagaoka I.; ''Epithelial cell-derived human beta-defensin-2 acts as a chemotaxin for mast cells through a pertussis toxin-sensitive and phospholipase C-dependent pathway.''; PubMed Europe PMC Scholia
6. Hill CP, Yee J, Selsted ME, Eisenberg D.; ''Crystal structure of defensin HNP-3, an amphiphilic dimer: mechanisms of membrane permeabilization.''; PubMed Europe PMC Scholia
7. García JR, Jaumann F, Schulz S, Krause A, Rodríguez-Jiménez J, Forssmann U, Adermann K, Klüver E, Vogelmeier C, Becker D, Hedrich R, Forssmann WG, Bals R.; ''Identification of a novel, multifunctional beta-defensin (human beta-defensin 3) with specific antimicrobial activity. Its interaction with plasma membranes of Xenopus oocytes and the induction of macrophage chemoattraction.''; PubMed Europe PMC Scholia
8. Garcia-Lopez G, Flores-Espinosa P, Zaga-Clavellina V.; ''Tissue-specific human beta-defensins (HBD)1, HBD2, and HBD3 secretion from human extra-placental membranes stimulated with Escherichia coli.''; PubMed Europe PMC Scholia
9. Jin MS, Kim SE, Heo JY, Lee ME, Kim HM, Paik SG, Lee H, Lee JO.; ''Crystal structure of the TLR1-TLR2 heterodimer induced by binding of a tri-acylated lipopeptide.''; PubMed Europe PMC Scholia
10. Harder J, Bartels J, Christophers E, Schroder JM.; ''Isolation and characterization of human beta -defensin-3, a novel human inducible peptide antibiotic.''; PubMed Europe PMC Scholia
11. Ganz T.; ''Defensins: antimicrobial peptides of innate immunity.''; PubMed Europe PMC Scholia
12. Lehrer RI.; ''Primate defensins.''; PubMed Europe PMC Scholia
13. Yang D, Chen Q, Chertov O, Oppenheim JJ.; ''Human neutrophil defensins selectively chemoattract naive T and immature dendritic cells.''; PubMed Europe PMC Scholia
14. Zhang XL, Selsted ME, Pardi A.; ''NMR studies of defensin antimicrobial peptides. 1. Resonance assignment and secondary structure determination of rabbit NP-2 and human HNP-1.''; PubMed Europe PMC Scholia
15. Wilde CG, Griffith JE, Marra MN, Snable JL, Scott RW.; ''Purification and characterization of human neutrophil peptide 4, a novel member of the defensin family.''; PubMed Europe PMC Scholia
16. Valore EV, Park CH, Quayle AJ, Wiles KR, McCray PB, Ganz T.; ''Human beta-defensin-1: an antimicrobial peptide of urogenital tissues.''; PubMed Europe PMC Scholia
17. Porter EM, Liu L, Oren A, Anton PA, Ganz T.; ''Localization of human intestinal defensin 5 in Paneth cell granules.''; PubMed Europe PMC Scholia
18. Lehrer RI, Barton A, Daher KA, Harwig SS, Ganz T, Selsted ME.; ''Interaction of human defensins with Escherichia coli. Mechanism of bactericidal activity.''; PubMed Europe PMC Scholia
19. de Leeuw E, Li C, Zeng P, Li C, Diepeveen-de Buin M, Lu WY, Breukink E, Lu W.; ''Functional interaction of human neutrophil peptide-1 with the cell wall precursor lipid II.''; PubMed Europe PMC Scholia
20. Hadjicharalambous C, Sheynis T, Jelinek R, Shanahan MT, Ouellette AJ, Gizeli E.; ''Mechanisms of alpha-defensin bactericidal action: comparative membrane disruption by Cryptdin-4 and its disulfide-null analogue.''; PubMed Europe PMC Scholia
21. Röhrl J, Yang D, Oppenheim JJ, Hehlgans T.; ''Human beta-defensin 2 and 3 and their mouse orthologs induce chemotaxis through interaction with CCR2.''; PubMed Europe PMC Scholia
22. Gullberg U, Bengtsson N, Bülow E, Garwicz D, Lindmark A, Olsson I.; ''Processing and targeting of granule proteins in human neutrophils.''; PubMed Europe PMC Scholia
23. Paone G, Wada A, Stevens LA, Matin A, Hirayama T, Levine RL, Moss J.; ''ADP ribosylation of human neutrophil peptide-1 regulates its biological properties.''; PubMed Europe PMC Scholia
24. Harwig SS, Park AS, Lehrer RI.; ''Characterization of defensin precursors in mature human neutrophils.''; PubMed Europe PMC Scholia
25. Wimley WC, Selsted ME, White SH.; ''Interactions between human defensins and lipid bilayers: evidence for formation of multimeric pores.''; PubMed Europe PMC Scholia
26. Ganz T, Liu L, Valore EV, Oren A.; ''Posttranslational processing and targeting of transgenic human defensin in murine granulocyte, macrophage, fibroblast, and pituitary adenoma cell lines.''; PubMed Europe PMC Scholia
27. Yang D, Chertov O, Bykovskaia SN, Chen Q, Buffo MJ, Shogan J, Anderson M, Schröder JM, Wang JM, Howard OM, Oppenheim JJ.; ''Beta-defensins: linking innate and adaptive immunity through dendritic and T cell CCR6.''; PubMed Europe PMC Scholia
28. Ganz T, Selsted ME, Szklarek D, Harwig SS, Daher K, Bainton DF, Lehrer RI.; ''Defensins. Natural peptide antibiotics of human neutrophils.''; PubMed Europe PMC Scholia
29. Lehrer RI, Ganz T.; ''Defensins: endogenous antibiotic peptides from human leukocytes.''; PubMed Europe PMC Scholia
30. Ghosh D, Porter E, Shen B, Lee SK, Wilk D, Drazba J, Yadav SP, Crabb JW, Ganz T, Bevins CL.; ''Paneth cell trypsin is the processing enzyme for human defensin-5.''; PubMed Europe PMC Scholia
31. Funderburg N, Lederman MM, Feng Z, Drage MG, Jadlowsky J, Harding CV, Weinberg A, Sieg SF.; ''Human -defensin-3 activates professional antigen-presenting cells via Toll-like receptors 1 and 2.''; PubMed Europe PMC Scholia

History

External references

DataNodes

Name	Type	Database reference	Comment
ART1	Protein	P52961 (Uniprot-TrEMBL)
Alpha-defensin dimers:anionic phospholipids	Complex	R-HSA-1471345 (Reactome)
Alpha-defensin dimers	Complex	R-HSA-1471331 (Reactome)
Alpha-defensin pore complex	Complex	R-HSA-1471355 (Reactome)
Alpha-defensins	Protein	R-HSA-1471333 (Reactome)
Anionic phospholipids	Metabolite	CHEBI:62643 (ChEBI)
Anionic phospholipids		CHEBI:62643 (ChEBI)
Beta defensin 103:TLR1:TLR2	Complex	R-HSA-1974673 (Reactome)
Beta defensins 1,4A,103	Protein	R-HSA-1973976 (Reactome)
Beta defensins 4A,103:CCR2	Complex	R-HSA-1973966 (Reactome)
Beta defensins 4A,103	Protein	R-HSA-1973973 (Reactome)
Beta-defensins 1,4A,103:CCR6	Complex	R-HSA-1471343 (Reactome)
Beta-defensins:anionic phospholipids	Complex	R-HSA-1471372 (Reactome)
Beta-defensins	Protein	R-HSA-1471310 (Reactome)
Beta-defensins	Protein	R-HSA-975681 (Reactome)
CCR2	Protein	P41597 (Uniprot-TrEMBL)
CCR2	Protein	P41597 (Uniprot-TrEMBL)
CCR6	Protein	P51684 (Uniprot-TrEMBL)
CCR6	Protein	P51684 (Uniprot-TrEMBL)
CD4	Protein	P01730 (Uniprot-TrEMBL)
CD4	Protein	P01730 (Uniprot-TrEMBL)
DEFA1(65-94)	Protein	P59665 (Uniprot-TrEMBL)
DEFA1(65-94)	Protein	P59665 (Uniprot-TrEMBL)
DEFA1(66-94)	Protein	P59665 (Uniprot-TrEMBL)
DEFA3(65-94)	Protein	P59666 (Uniprot-TrEMBL)
DEFA3(66-94)	Protein	P59666 (Uniprot-TrEMBL)
DEFA4(64-96)	Protein	P12838 (Uniprot-TrEMBL)
DEFA5(20-94)	Protein	Q01523 (Uniprot-TrEMBL)
DEFA5(?-94)	Protein	Q01523 (Uniprot-TrEMBL)
DEFA5(?-94)	Protein	Q01523 (Uniprot-TrEMBL)
DEFA6(?-100)	Protein	Q01524 (Uniprot-TrEMBL)
DEFB1(?-68)	Protein	P60022 (Uniprot-TrEMBL)
DEFB103A(23-67)	Protein	P81534 (Uniprot-TrEMBL)
DEFB103A(23-67)	Protein	P81534 (Uniprot-TrEMBL)
DEFB4A(?-64)	Protein	O15263 (Uniprot-TrEMBL)
Defensins alpha 1-3:CD4	Complex	R-HSA-1471352 (Reactome)
Defensins alpha 1-3	Protein	R-HSA-1471337 (Reactome)
Defensins alpha 1-4	Protein	R-HSA-1470042 (Reactome)
Defensins alpha 1-4	Protein	R-HSA-1470049 (Reactome)
Defensins alpha 1-4	Protein	R-HSA-1471313 (Reactome)
Defensins that bind Lipid II:Lipid II	Complex	R-HSA-1471328 (Reactome)
Defensins that bind Lipid II	Protein	R-HSA-1973970 (Reactome)
HNP1-3:gp120	Complex	R-NUL-1471336 (Reactome)
Lipid II	Metabolite	CHEBI:27692 (ChEBI)
Lipid II	Metabolite	CHEBI:27692 (ChEBI)
Pre-pro-defensins	Protein	R-HSA-1467262 (Reactome)
Pro-defensins alpha 1-4	Protein	R-HSA-1470043 (Reactome)
Pro-defensins	Protein	R-HSA-1467213 (Reactome)
Surface protein gp120	Protein	P04578 (Uniprot-TrEMBL)
TLR1(19-786)	Protein	Q5FWG5 (Uniprot-TrEMBL)
TLR1:TLR2	Complex	R-HSA-168946 (Reactome)
TLR2	Protein	O60603 (Uniprot-TrEMBL)
Trypsin 2, 3	Protein	R-HSA-1460242 (Reactome)
omega-N-(ADP-ribosyl)-L-arginine-DEFA1(65-94)	Protein	P59665 (Uniprot-TrEMBL)

Annotated Interactions

Source	Target	Type	Database reference	Comment
ART1		mim-catalysis	R-HSA-1972385 (Reactome)
	Alpha-defensin dimers:anionic phospholipids	Arrow	R-HSA-1461971 (Reactome)
Alpha-defensin dimers:anionic phospholipids			R-HSA-1461982 (Reactome)
	Alpha-defensin dimers	Arrow	R-HSA-1462014 (Reactome)
Alpha-defensin dimers			R-HSA-1461971 (Reactome)
	Alpha-defensin pore complex	Arrow	R-HSA-1461982 (Reactome)
Alpha-defensins			R-HSA-1462014 (Reactome)
Anionic phospholipids			R-HSA-1461971 (Reactome)
Anionic phospholipids			R-HSA-1467269 (Reactome)
	Beta defensin 103:TLR1:TLR2	Arrow	R-HSA-1974676 (Reactome)
Beta defensins 1,4A,103			R-HSA-1471338 (Reactome)
	Beta defensins 4A,103:CCR2	Arrow	R-HSA-1973968 (Reactome)
Beta defensins 4A,103			R-HSA-1973968 (Reactome)
	Beta-defensins 1,4A,103:CCR6	Arrow	R-HSA-1471338 (Reactome)
	Beta-defensins:anionic phospholipids	Arrow	R-HSA-1467269 (Reactome)
	Beta-defensins	Arrow	R-HSA-1471322 (Reactome)
Beta-defensins			R-HSA-1467269 (Reactome)
Beta-defensins			R-HSA-1471322 (Reactome)
CCR2			R-HSA-1973968 (Reactome)
CCR6			R-HSA-1471338 (Reactome)
CD4			R-HSA-1471314 (Reactome)
DEFA1(65-94)			R-HSA-1972385 (Reactome)
	DEFA5(20-94)	Arrow	R-HSA-1461995 (Reactome)
	DEFA5(20-94)	Arrow	R-HSA-1462005 (Reactome)
DEFA5(20-94)			R-HSA-1461993 (Reactome)
DEFA5(20-94)			R-HSA-1461995 (Reactome)
DEFA5(20-94)			R-HSA-1462005 (Reactome)
	DEFA5(?-94)	Arrow	R-HSA-1461993 (Reactome)
DEFB103A(23-67)			R-HSA-1974676 (Reactome)
	Defensins alpha 1-3:CD4	Arrow	R-HSA-1471314 (Reactome)
Defensins alpha 1-3			R-HSA-1471314 (Reactome)
Defensins alpha 1-3			R-HSA-1471354 (Reactome)
	Defensins alpha 1-4	Arrow	R-HSA-1462003 (Reactome)
	Defensins alpha 1-4	Arrow	R-HSA-1462039 (Reactome)
	Defensins alpha 1-4	Arrow	R-HSA-1462041 (Reactome)
Defensins alpha 1-4			R-HSA-1462003 (Reactome)
Defensins alpha 1-4			R-HSA-1462041 (Reactome)
	Defensins that bind Lipid II:Lipid II	Arrow	R-HSA-1467209 (Reactome)
Defensins that bind Lipid II			R-HSA-1467209 (Reactome)
	HNP1-3:gp120	Arrow	R-HSA-1471354 (Reactome)
Lipid II			R-HSA-1467209 (Reactome)
Pre-pro-defensins			R-HSA-1462023 (Reactome)
Pro-defensins alpha 1-4			R-HSA-1462039 (Reactome)
	Pro-defensins	Arrow	R-HSA-1462023 (Reactome)
			R-HSA-1461971 (Reactome)	The alpha-defensin dimers adsorb onto microbial membrane anionic phospholipids, represented here as a complex of alpha-defensin dimers and a representative set of phospholipid molecules 'membrane anionic phospholipids'. The polar topology of defensins, with their spatially separated charged and hydrophobic regions, allows them to insert into microbial cell membranes, which contains more negatively charged phospholipids than mammalian cell membranes (Lohner et al. 1997). Defensins permeabilize membrane vesicles (Lehrer et al. 1989) with a greater effect on vesicles rich in negatively charged phospholipids (Fuji et al. 1993, Wimley et al. 1994).
			R-HSA-1461982 (Reactome)	Once adsorbed/inserted into the membrane, alpha defensins are believed to aggregate into pore forming structures. Based on vesicle leakage and dextran permeability experiments, Wimley et al. (1994) proposed a multimeric pore model consisting of 6-8 defensin dimers which come together to form a large pore with inner diameter of 2-2.5nm. More recently using solid-state NMR and artificial lipid bilayers, Zhang et al. (2010) provide evidence of a dimer pore model in which the polar top of the dimer lines an aqueous pore while the hydrophobic bottom faces the lipid chains. Regardless of the exact conformation, the resulting pores then allow the efflux of essential microbial cell components.
			R-HSA-1461993 (Reactome)	Pro HD5 is stored and secreted from granules of Paneth cells in the small intestine (Porter et al. 1997, Cunliffe et al. 2001). The serine protease tryspin colocalizes to these granules as the inactive zymogen trypsinogen. Removal of the defensin propiece occurs extracellularly after release in to the crypt lumen, and is mediated by trypsin 2 (anionic trypsin) and/or trypsin-3 (mesotrypsin) which are converted to their active forms by enteroprotease like enzymes or by autoactivation (Ghosh et al. 2002, Ouelette 2011).
			R-HSA-1461995 (Reactome)	Pro-defensin alpha 5 is stored in the granules of Paneth cells in the small intestine (Porter et al. 1997). This pro-peptide has some antimicrobial activity but is not as effective as the mature peptide (Ghosh et al. 2002).
			R-HSA-1462003 (Reactome)	Alpha defensins HNP1-4, the neutrophil defensins, are stored in biologically active form in neutrophil primary (azurophil) granules, where they make up 5-10% of total cellular protein in these cells (Lehrere et al. 1993). The relative amounts of peptide for HNP-1 to -3 are 2:2:1 with HNP-4 being only a minor component.
			R-HSA-1462005 (Reactome)	Pro defensin alpha 5 is secreted from the storage granules of Paneth cells in the small intestine (Porter et al. 1997).
			R-HSA-1462014 (Reactome)	The crystal structure of human alpha-defensin HNP-3 revealed that it forms a dimer containing a six-stranded beta-sheet region (Hill et al. 1991). NMR studies indicate that HNP-1 can also form dimers or higher-order aggregates in solution and artificial lipid bilayers (Zhang et al. 1992, 2010a, 2010b). Models of alpha and beta defensins suggest that dimerization and/or higher order structures are characteristic, though not univeral or required for the biological effects of some beta-defensins (Suresh & Verma 2006, Pazgier et al. 2006).
			R-HSA-1462023 (Reactome)	Pre-pro-defensins are cleaved in the golgi by undefined proteases which remove the signal peptide (Yang et al. 2004, Pazgier et al. 2006). Subsequently, alpha-defensins are cleaved again to produce the biologically active mature peptide. Beta defensins have much shorter propieces and may be active once the signal peptide is removed. Further N-terminal processing of the mature defensin may yield multiple forms of the same peptide (Pazgier et al. 2006).
			R-HSA-1462039 (Reactome)	Synthesis of alpha defensins takes place in neutrophil precursor cells, the promyelocytes, in the bone marrow. Pro HNP1-4 are cleaved in the Golgi body, with HNP-2 being derived from cleavage of the N-terminal amino acid from HNP-1 or HNP-3. The defensin propiece is not only important for correct sub-cellular trafficking and sorting but also inhibits HNP activity (Valore et al. 1996, Wu et al. 2007). The resulting mature peptides are sorted to primary neutrophil (azurophil) granules for storage (Valore & Ganz 1992, Harwig et al. 1992, Cowland & Borregaard).
			R-HSA-1462041 (Reactome)	Human neutrophils contain thousands of cytoplasmic granules. These membrane-bound organelles act as storage compartments destined for secretion or in the case of azurophil granules, destined for fusion with phagosomes. A small amount of defensin, but perhaps not enough for antimicrobial activity, may be released extracellularly by neutrophils (Ganz 1987).
			R-HSA-1467209 (Reactome)	In S. aureus, rather than cause gross membrane changes, HNP-1 (de Leeuw et al. 2010) and hBD3 (Sass et al. 2011) appear to interfere with cell wall biosynthetic pathways by binding to Lipid II (undecaprenylpyrophosphate-MurNAc[pentapeptide]-GlcNAc), an essential precursor of bacterial cell walls and the target of several antibiotics (Breukink & de Krujiff 2007). The transformation of monomeric lipid II into a polymeric peptidoglycan by the bifunctional S. aureus enzyme Penicillin-binding protein 2 (PBP2) is inhibited by hBD3 (Sass et al. 2011) resulting in local lesions of the cell wall layer through which membranes and cytoplasmic contents ultimately protrude.
			R-HSA-1467269 (Reactome)	Binding and disruption of microbial membranes is widely believed to be the primary mechanism of action for beta-defensins. There is no direct evidence of this, but a growing number of studies support this model (Pazgier et al. 2006). Beta-defensins have antimicrobial properties that correlate with membrane permeabilization effects (Antcheva et al. 2004, Sahl et al. 2005, Yenugu et al. 2004). The sensitivity of microbes to beta-defensins correlates with the lipid composition of the membrane; more negatively-charged lipids correlate with larger beta-defensin 103-induced changes in membrane capacitance (Bohling et al. 2006). Beta-defensin-103 was observed to give rise to ionic currents in Xenopus membranes (Garcia et al. 2001) and cell wall perforation was observed in S. aureus when treated with HBD-3 (Harder et al. 2001). Two models explain how membrane disruption takes place. The 'pore model' postulates that beta-defenisns form transmembrane pores in a similar manner to alpha-defensins, while the 'carpet model' suggests that beta-defensins act as detergents, causing a less organised disruption. Beta-defensins have a structure that is topologically distinct from that of alpha-defensins, suggesting a different mode of dimerization and an electrostatic charge-based mechanism of membrane permeabilization rather than a mechanism based on formation of bilayer-spanning pores (Hoover et al. 2000).
			R-HSA-1471314 (Reactome)	Alpha-defensins, theta-defensins and their synthetic analogues the retrocyclins have been shown in numerous studies to have anti-HIV-1 activity (Chang & Klotman 2004). This appears to be mediated via multiple mechanisms including direct viral inactivation and down regulation of host-cell target co-receptors important for viral entry (Furci et al. 2007, Seidel et al. 2010). Further, HNPs 1 3, act as lectins and bind with relatively high affinity to gp120 (KD range, 15.8-52.8 nM) on the HIV-1 envelope and CD4 (KD range, 8.0-34.9 nM) on host target cells, both important molecules for viral entry (Wang et al. 2004). Artificial theta defensins, the retrocyclins, predicted from the human pseudogenes bind with even higher affinity whereas HNP-4 binding is much weaker (Wu et al. 2005). Alpha defensins have been demonstrated to inhibit the binding of gp120 to CD4 thus blocking HIV-1 fusion with its target cells (Furci et al. 2007).
			R-HSA-1471322 (Reactome)	Beta defensin precursors are more simple in structure than those of alpha defensins, having a signal sequence, a short or absent propiece and the mature defensin sequence at the C-terminus. The signal sequence is cleaved off by a signal peptidase in the endoplasmic reticulum (Ganz 2003). Mature beta defensins 1, 2, 3, and 4 are secreted primarily by epithelial cells but are also produced by some immune cells such as monocytes, macrophages and dendritic cells (Duits et al. 2000, Ryan et al. 2003).
			R-HSA-1471338 (Reactome)	The chemotactic activity of beta-defensins 1, 4A and 103 (hBD1-3) for immune and inflammatory cells such as memory T cells and immature dendritic cells is mediated through binding to the chemokine receptor CCR6.
			R-HSA-1471354 (Reactome)	Alpha-defensins, theta-defensins and their synthetic analogues the retrocyclins have been shown in numerous studies to have anti-HIV-1 activity (Chang & Klotman 2004). This appears to be mediated via multiple mechanisms including direct viral inactivation and down regulation of host-cell target co-receptors important for viral entry (Furci et al. 2007, Seidel et al. 2010). HNP1-3 act as lectins, binding with relatively high affinity to gp120 (KD range, 15.8-52.8 nM) on the HIV-1 envelope and CD4 (KD range, 8.0-34.9 nM) on host target cells, both important molecules for viral entry (Wang et al. 2004). Retrocyclins, artificial theta defensins predicted from human defensin pseudogenes, bind with even higher affinity whereas HNP-4 binding is much weaker (Wu et al. 2005). Alpha defensins have been demonstrated to inhibit the binding of gp120 to CD4 thus blocking HIV-1 fusion with its target cells (Furci et al. 2007).
			R-HSA-1972385 (Reactome)	HNP-1 is recognized as a substrate by arginine-specific ADP-ribosyltransferase-1 which ribosylates Arg-14 of the peptide. The modified defensin has reduced antimicrobial and cytotoxic activities but its chemotactic properties remain unchanged whilst its ability to induced the chemokine IL-8 is enhanced.
			R-HSA-1973968 (Reactome)	human beta-defensin (hBD)4A and 103 interact with CCR2, a chemokine receptor expressed on monocytes, macrophages, and neutrophils.
			R-HSA-1974676 (Reactome)	Beta defensin 103 (hBD-3) can induce expression of the costimulatory molecules CD80, CD86 and CD40 on monocytes and myeloid dendritic cells in a Toll-like receptor (TLR)-dependent manner. Activation by hBD-3 is mediated by an interaction that requires TLRs 1 and 2 (Funderburg et al. 2007, 2011).
TLR1:TLR2			R-HSA-1974676 (Reactome)
Trypsin 2, 3		mim-catalysis	R-HSA-1461993 (Reactome)
	omega-N-(ADP-ribosyl)-L-arginine-DEFA1(65-94)	Arrow	R-HSA-1972385 (Reactome)