Heparanase-Induced Activation of AKT Stabilizes b-Catenin and Modulates Wnt/b-Catenin Signaling during Herpes Simplex Virus 1 Infection

Lulia Koujah, Krishnaraju Madavaraju, Alex M. Agelidis, Chandrashekhar D. Patil, Deepak Shukla

Research output: Contribution to journalArticlepeer-review

3 Scopus citations

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 b-catenin signal transduction. The regulatory role of HPSE on the activation, nuclear translocation, and signal transduction of b-catenin disrupts cellular homeostasis and establishes a pathogenic environment that promotes viral replication. Under normal physiological conditions, b-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 b-catenin through (i) the release of b-catenin from the destruction complex, and (ii) direct phosphorylation of b-catenin at Ser552. This study also provides an in-depth characterization of the proviral role of b-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 b-catenin signaling in HSV-1 infection. IMPORTANCE Heparanase (HPSE) and b-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.

Original languageEnglish
Article numbere02792-21
JournalmBio
Volume12
Issue number6
DOIs
StatePublished - 1 Dec 2021
Externally publishedYes

Keywords

  • Herpes simplex virus
  • Host-pathogen interactions
  • Wnt signaling

ASJC Scopus subject areas

  • Microbiology
  • Virology

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