Versatile whey acidic protein four-disulfide core domain proteins: biology and role in diseases

Abstract

The Whey acidic protein four-disulfide core (WFDC) protein family consists of proteins with one or more WFDC domains which are ubiquitously expressed throughout the body of human and perform a wide range of functions, including antiprotease, antibacterial, and immunomodulatory functions. Aberrant expression of WFDC proteins is associated with human diseases. However, review on the WFDC protein family is limited and insufficient. Furthermore, a systematic summary of the underlying mechanisms of WFDC protein activity is lacking. In this review, we give a summary of the structural basis and molecular function of these proteins and review the immune regulatory mechanisms and signaling pathways of WFDC proteins in the development of certain diseases. Furthermore, we discuss the diagnostic and prognostic potential of multiple WFDC proteins in the aforementioned conditions, as well as their prospective use. At last, we also discuss the progress of WFDC protein in clinical trials and put forward some research difficulties and the directions of follow-up research. Our review highlights the functional diversity and clinical significance of WFDC proteins family, while providing potential targets for drug development and innovative therapeutic strategies, this review lays the foundation and direction for future research on WFDC proteins.

Keywords: WFDC proteins; biomarker; cancer; heart failure; inflammatory disease; signaling/signaling pathways.

FIGURE 1

This figure shows the positions of the disulfide bonds in WFDC domain of human WFDC proteins, except for WFDC9, WFDC10B, WFDC11, and ANOS1, due to insufficient data. And the information is obtained from UniProt. Created with BioRender.com.

FIGURE 2

The functions of WFDC proteins, including WFDC4, WFDC14, WFDC12 and WFDC2. Among them, WFDC4 and WFDC14 have antiprotease, antibacterial, antiviral, and immunomodulatory functions. For WFDC12, it shows the antiprotease and immunomodulatory activity. And WFDC2 can inhibit several proteases and bacteria. Created with BioRender.com.

FIGURE 3

The biological functions of WFDC proteins are involved in several molecular mechanisms. For the anti-HIV ability, WFDC4 can bind to annexin Ⅱ, which is a cofactor for the HIV-1 infection. And in the immunomodulatory function, WFDC4 and WFDC14 can inhibit the responses mediated by LPS. Extracellularly, WFDC4 can neutralize the LPS as well as WFDC14. And intracellularly, the degradation of IκBα which will activate the NF-κB pathway can be inhibited by WFDC4 and WFDC14. Moreover, WFDC4 can competitively bind to NF-κB DNA sites at the gene promoter regions to inhibit the related gene expression. TLR4, toll-like receptor 4. GCK, germinal center kinase. Created with BioRender.com.

FIGURE 4

WFDC protein plays a role in the regulation of cancer. For WFDC4, it can increase the expression of PI3K and p-AKT, which subsequently activate the NF-κB and MAPK signaling pathway to promote cancer progression and metastasis. When it comes to WFDC2, it has an effect on the JAK/STAT pathway to increase the EMT. Meanwhile, HDAC3 can induce the expression of WFDC2 and then bind to it to stimulate the GSK-3β and the NF-κB pathway. But extracellularly, WFDC2 can bind to EGFR and inhibit its phosphorylation, which will inhibit the expression of snails. Then this may improve the E-cadherin expression to inhibit the cancer metastasis. HDAC3, histone deacetylase 3. Created with BioRender.com.