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Heparanase-Induced Activation of AKT Stabilizes β-Catenin and Modulates Wnt/β-Catenin Signaling during Herpes Simplex Virus 1 Infection.
- Source :
-
MBio [mBio] 2021 Dec 21; Vol. 12 (6), pp. e0279221. Date of Electronic Publication: 2021 Nov 09. - Publication Year :
- 2021
-
Abstract
- Under pathological conditions like herpes simplex virus 1 (HSV-1) infection, host-pathogen interactions lead to major reconstruction of the host protein network, which contributes to the dysregulation of signaling pathways and disease onset. Of note is the upregulation of a multifunctional host protein, heparanase (HPSE), following infection, which serves as a mediator in HSV-1 replication. In this study, we identify a novel function of HPSE and highlight it as a key regulator of β-catenin signal transduction. The regulatory role of HPSE on the activation, nuclear translocation, and signal transduction of β-catenin disrupts cellular homeostasis and establishes a pathogenic environment that promotes viral replication. Under normal physiological conditions, β-catenin is bound to a group of proteins, referred to as the destruction complex, and targeted for ubiquitination and, ultimately, degradation. We show that virus-induced upregulation of HPSE leads to the activation of Akt and subsequent stabilization and activation of β-catenin through (i) the release of β-catenin from the destruction complex, and (ii) direct phosphorylation of β-catenin at Ser552. This study also provides an in-depth characterization of the proviral role of β-catenin signaling during HSV-1 replication using physiologically relevant cell lines and in vivo models of ocular infection. Furthermore, pharmacological inhibitors of this pathway generated a robust antiviral state against multiple laboratory and clinical strains of HSV-1. Collectively, our findings assign a novel regulatory role to HPSE as a driver of β-catenin signaling in HSV-1 infection. IMPORTANCE Heparanase (HPSE) and β-catenin have independently been implicated in regulating key pathophysiological processes, including neovascularization, angiogenesis, and inflammation; however, the relationship between the two proteins has remained elusive thus far. For that reason, characterizing this relationship is crucial and can lead to the development of novel therapeutics. For HSV-1 specifically, current antivirals are not able to abolish the virus from the host, leaving patients susceptible to episodes of viral reactivation. Identifying a host-based intervention can provide a better alternative with enhanced efficacy and sustained relief.
- Subjects :
- Amino Acid Motifs
Cell Line
Glucuronidase genetics
Herpes Simplex genetics
Herpes Simplex metabolism
Herpes Simplex virology
Herpesvirus 1, Human genetics
Host-Pathogen Interactions
Humans
Phosphorylation
Proto-Oncogene Proteins c-akt genetics
Virus Activation
Virus Replication
Wnt Signaling Pathway
beta Catenin chemistry
beta Catenin genetics
Glucuronidase metabolism
Herpes Simplex enzymology
Herpesvirus 1, Human physiology
Proto-Oncogene Proteins c-akt metabolism
beta Catenin metabolism
Subjects
Details
- Language :
- English
- ISSN :
- 2150-7511
- Volume :
- 12
- Issue :
- 6
- Database :
- MEDLINE
- Journal :
- MBio
- Publication Type :
- Academic Journal
- Accession number :
- 34749529
- Full Text :
- https://doi.org/10.1128/mBio.02792-21