Alterations in Immune-Related Defensin Alpha 4 (DEFA4) Gene Expression in Health and Disease

Abstract

Defensin Alpha 4 (DEFA4) is the fourth member of the Alpha Defensins family known as a part of antimicrobial peptides in the innate immune system. DEFA4 has a strong preference to kill Gram-negative bacteria more than Gram-positive bacteria. In addition, DEFA4 exhibits antiviral activity against human immunodeficiency virus type 1 (HIV-1) in vitro. Moreover, DEFA4 can act as an inhibitor of corticosterone production (Corticostatin). On the other hand, alternations in DEFA4 gene expression have been reported in different disorders such as diseases related to inflammation and immunity dysfunction, brain-related disorders, and various cancers. The up-regulation of DEFA4 appears to be involved in the malignant transformation or aggressive form of cancer. Interestingly, the modified version of DEFA4 fragment (1-11) was potent and efficient against antibiotic-resistant bacteria. This review provides a general background abSaudi Arabia out DEFA4 and sheds light on changes in DEFA4 gene expression in different diseases. The paper also discusses other aspects related to DEFA4 as an antimicrobial and antiviral agent. The research was conducted based on available articles obtained from databases starting from 1988 to the present.

Figure 1

This figure shows the structure-related DEFA4 properties. Created with BioRender.com. (a) Alignments of the amino acid sequences that show conserved residues: 6 Cysteine residues (C) are shown in yellow; Glycine (G) is colored in green, Arginine (R) is located after the second Cysteine, Glutamic acid (E). Positively-charged residues are colored in blue, negatively-charged residues are colored in red. Relative to DEFA1–3 (+3), DEFA4 is the higher positive charge of (+4). This figure also shows the bonds that stabilize the α-defensins tertiary structure, 3 disulfide bridges between 6 conserved (C) and one salt bridge formed by the side chains of R and (E). (b) Three clustered cationic residues of Arginine (Arg10, Arg11, Arg15). (c) DEFA4 consists of three beta-sheets (B) arranged into an antiparallel structure. B1and B2 are connected by the long loop (T1), and beta-hairpin (T2) is formed by B2 and B3. DEFA4 forms homodimers [46].

Figure 2

Milestone reports that have contributed to describing DEFA4 properties over the years. Created with BioRender.com.

Figure 3

DEFA4 cytogenetic location in the human genome (8p23.1.), DEFA4 gene is therein located on the short arm (p) of chromosome 8 at position 2, band 3, sub-band 1.