WFDC1/ps20: A host factor that influences the neutrophil response to murine hepatitis virus (MHV) 1 infection

Rogers, Erin; Wang, Ben X.; Cui, Zhu; Rowley, David R.; Ressler, Steven J.; Vyakarnam, Annapurna; Fish, Eleanor N.

doi:10.1016/j.antiviral.2012.08.012

Cited by 7 publications

(4 citation statements)

References 36 publications

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“…In contrast, exogenous addition of recombinant PS20 protein or ectopic forced expression of WFDC1 improves HIV transfer 33 . Consistently, neutrophils isolated from wfdc1/ps20 deficient mice were found to be more susceptible to mouse hepatitis virus strain 1 (MHV‐1) infection compared to neutrophils isolated from normal ps20 mice 34 . Collectively, these findings suggest a modulating role of WFDC1 in the pathogenesis of HIV infectivity.…”

Section: The Role Of Wfdc1 In Inflammation and Infectionmentioning

confidence: 72%

Molecular structure, gene expression and functional role of WFDC1 in angiogenesis and cancer

Zhu

Bennett

et al. 2021

Cell Biochemistry & Function

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Whey acidic proteins (WAP) perform a diverse range of important biological functions, including proteinase activity, calcium transport and bacterial growth. The WAP four‐disulphide core domain protein 1 (WFDC1) gene (also called PS20), encodes the 20 kDa prostate stromal protein (ps20), which is a member of the WAP‐type four‐disulphide core domain family of proteins, and exhibits characteristics of serine protease inhibitors, such as elafin and secretory leukocyte protease inhibitor. Molecular structural analysis reveals that ps20 consists of four‐disulphide bonds formed by eight cysteine residues located at the carboxyl terminus of the protein. Wfdc1‐null mice were found to display no overt developmental phenotype, suggesting a dispensable role in organ growth and development. However, WFDC1 was able to mediate endothelial cell migration and pericyte stabilization, which are vital for the formation of functional vascular structures. WFDC1 was also found to be downregulated in cancers and exhibited a regulatory effect on cell proliferation. In addition, it was involved in the modulation of memory T cells during human immunodeficiency virus infection. Gaining a solid understanding of the mechanisms by which WFDC1 regulates tissue homeostasis and disease processes, in a tissue specific manner, will be an important move towards the development of WFDC1/ps20 as potential therapeutic targets.

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Section: The Role Of Wfdc1 In Inflammation and Infectionmentioning

confidence: 72%

Molecular structure, gene expression and functional role of WFDC1 in angiogenesis and cancer

Zhu

Bennett

et al. 2021

Cell Biochemistry & Function

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“…Lastly, while it is clear then that CL can cleave ps20 at the C-terminus, and this may play a role in regulating interactions with ECM components, it is possible that CL cleavage of ps20 may also have as yet unidentified functions. In light of the numerous indications that ps20 possesses pleiotropic functionality [3] , [4] , [5] , [9] , [13] , [33] , it may be the case that CL and possibly other proteases regulate the function of ps20 through tissue and cell-type specific cleavage events by i) generating functional protein fragments, or ii) abrogating interactions with other tissue components, such as fibronectin.…”

Section: Discussionmentioning

confidence: 99%

“…Members possess pleiotropic roles in the inhibition of inflammatory proteases, abrogation of microbial growth, and the ability to regulate the responses to viral infections [1] , [2] . ps20 is a WFDC family member for which no protease inhibitory function has yet been elucidated, but nonetheless possesses potent immune regulatory functions including the modulation of cell and molecular responses to viral infection and wounding [2] , [3] , [4] . Other data show ps20 to be a physiologically pleiotropic protein able to regulate numerous downstream host factors such as ICAM-1 and IL-8 with effects on processes as diverse as tumourigenesis and HIV infectivity [3] , [5] .…”

Section: Introductionmentioning

confidence: 99%

Cathepsin-L and transglutaminase dependent processing of ps20: A novel mechanism for ps20 regulation via ECM cross-linking

Hickman

Galustian

Smith

et al. 2016

Biochemistry and Biophysics Reports

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Whey-acidic-protein (WAP) four-disulphide core (WFDC) proteins have important roles in the regulation of innate immunity, anti-microbial function, and the inhibition of inflammatory proteases at mucosal surfaces. It was recently demonstrated that the WFDC protein, prostate stromal 20 (ps20), encoded by the WFDC1 gene, is a potent growth inhibitory factor, and shares with other WFDC proteins the ability to modulate wound healing processes and immune responses to viral infections. However, ps20 remains relatively uncharacterised at the protein level.Using a panel of ps20 antibodies for western-blotting (WB), ELISA and immunoaffinity purification, we isolated, biochemically characterised and tested ps20 preparations for three biological properties: (i) interactions with glycosaminoglycans (GAG) (ii) inhibition of cell proliferation, and (iii) transglutaminase2 (TG2) mediated crosslinking of ps20 to fibronectin, a process implicated in wound healing. We show herein that ps20 preparations contain multiple molecular forms including full-length ps20 (resolving at ≈27 kDa), an exon 3 truncated form (≈22 kDa) that lacks aa113–140, and variable amounts of a putatively cleaved lower MW (≈15–17 kDa) species. Untagged purified ps20 preparations containing a mixture of these forms are biologically active in significantly suppressing prostate cell proliferation. We show that one mechanism by which lower LMW forms of ps20 arise is through cathepsin L (CL) cleavage, and confirm that CL cleaves ps20 at the C-terminus, but this does not inhibit its growth inhibitory function. However, CL cleavage abrogated the interaction between ps20 and solid-phase fibronectin.Therefore, we demonstrate for the first time that LMW forms of ps20 that lack a C-terminal immunogenic epitope can arise through CL cleavage and this cleavage impairs multimerisation and potential capacity to cross-link to ECM, but not the capacity of ps20 to inhibit cell proliferation. We propose that ps20 like other WFDC proteins can become associated with GAGs and the ECM. Furthermore, we suggest post-translational processing and cleavage of ps20 is required to generate functional protein species, and TG2 mediated crosslinking and CL cleavage form components of a ps20 regulatory apparatus.

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“…Quantitative polymerase chain reaction (qPCR) was performed using the LightCycler FastStart DNA Master SYBR Green PLUS I kit (Roche) and a LightCycler (Roche), following the manufacturer’s protocol as described previously [ 34 ]. Primers for target IFN stimulated genes (ISGs; Table 1 ) were synthesized by ACGT Corporation.…”

Section: Methodsmentioning

confidence: 99%

A Conserved Residue, Tyrosine (Y) 84, in H5N1 Influenza A Virus NS1 Regulates IFN Signaling Responses to Enhance Viral Infection

Wang

Wei

Kotra

et al. 2017

Viruses

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The non-structural protein, NS1, is a virulence factor encoded by influenza A viruses (IAVs). In this report, we provide evidence that the conserved residue, tyrosine (Y) 84, in a conserved putative SH2-binding domain in A/Duck/Hubei/2004/L-1 [H5N1] NS1 is critical for limiting an interferon (IFN) response to infection. A phenylalanine (F) substitution of this Y84 residue abolishes NS1-mediated downregulation of IFN-inducible STAT phosphorylation, and surface IFNAR1 expression. Recombinant IAV (rIAV) [H1N1] expressing A/Grey Heron/Hong Kong/837/2004 [H5N1] NS1-Y84F (rWSN-GH-NS1-Y84F) replicates to lower titers in human lung epithelial cells and is more susceptible to the antiviral effects of IFN-β treatment compared with rIAV expressing the intact H5N1 NS1 (rWSN-GH-NS1-wt). Cells infected with rWSN-GH-NS1-Y84F express higher levels of IFN stimulated genes (ISGs) associated with an antiviral response compared with cells infected with rWSN-GH-NS1-wt. In mice, intranasal infection with rWSN-GH-NS1-Y84F resulted in a delay in onset of weight loss, reduced lung pathology, lower lung viral titers and higher ISG expression, compared with mice infected with rWSN-GH-NS1-wt. IFN-β treatment of mice infected with rWSN-GH-NS1-Y84F reduced lung viral titers and increased lung ISG expression, but did not alter viral titers and ISG expression in mice infected with rWSN-GH-NS1-wt. Viewed altogether, these data suggest that the virulence associated with this conserved Y84 residue in NS1 is, in part, due to its role in regulating the host IFN response.

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WFDC1/ps20: A host factor that influences the neutrophil response to murine hepatitis virus (MHV) 1 infection

Cited by 7 publications

References 36 publications

Molecular structure, gene expression and functional role of WFDC1 in angiogenesis and cancer

Molecular structure, gene expression and functional role of WFDC1 in angiogenesis and cancer

Cathepsin-L and transglutaminase dependent processing of ps20: A novel mechanism for ps20 regulation via ECM cross-linking

A Conserved Residue, Tyrosine (Y) 84, in H5N1 Influenza A Virus NS1 Regulates IFN Signaling Responses to Enhance Viral Infection

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