Disruption of innate defense responses by endoglycosidase HPSE promotes cell survival
Alex Agelidis, Benjamin A. Turturice, Rahul K. Suryawanshi, Tejabhiram Yadavalli, Dinesh Jaishankar, Joshua Ames, James Hopkins, Lulia Koujah, Chandrashekhar D. Patil, Satvik R. Hadigal, Evan J. Kyzar, Anaamika Campeau, Jacob M. Wozniak, David J. Gonzalez, Israel Vlodavsky, Jin-ping Li, David L. Perkins, Patricia W. Finn, Deepak Shukla
Alex Agelidis, Benjamin A. Turturice, Rahul K. Suryawanshi, Tejabhiram Yadavalli, Dinesh Jaishankar, Joshua Ames, James Hopkins, Lulia Koujah, Chandrashekhar D. Patil, Satvik R. Hadigal, Evan J. Kyzar, Anaamika Campeau, Jacob M. Wozniak, David J. Gonzalez, Israel Vlodavsky, Jin-ping Li, David L. Perkins, Patricia W. Finn, Deepak Shukla
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Research Article Cell biology Microbiology

Disruption of innate defense responses by endoglycosidase HPSE promotes cell survival

Abstract

The drive to withstand environmental stresses and defend against invasion is a universal trait extant in all forms of life. While numerous canonical signaling cascades have been characterized in detail, it remains unclear how these pathways interface to generate coordinated responses to diverse stimuli. To dissect these connections, we followed heparanase (HPSE), a protein best known for its endoglycosidic activity at the extracellular matrix but recently recognized to drive various forms of late-stage disease through unknown mechanisms. Using herpes simplex virus-1 (HSV-1) infection as a model cellular perturbation, we demonstrate that HPSE acts beyond its established enzymatic role to restrict multiple forms of cell-intrinsic defense and facilitate host cell reprogramming by the invading pathogen. We reveal that cells devoid of HPSE are innately resistant to infection and counteract viral takeover through multiple amplified defense mechanisms. With a unique grasp of the fundamental processes of transcriptional regulation and cell death, HPSE represents a potent cellular intersection with broad therapeutic potential.

Authors

Alex Agelidis, Benjamin A. Turturice, Rahul K. Suryawanshi, Tejabhiram Yadavalli, Dinesh Jaishankar, Joshua Ames, James Hopkins, Lulia Koujah, Chandrashekhar D. Patil, Satvik R. Hadigal, Evan J. Kyzar, Anaamika Campeau, Jacob M. Wozniak, David J. Gonzalez, Israel Vlodavsky, Jin-ping Li, David L. Perkins, Patricia W. Finn, Deepak Shukla

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Figure 6

Bioinformatics-guided analysis of transcription factor activation in viral infection identifies potent antiviral compounds.

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Bioinformatics-guided analysis of transcription factor activation in vir...
(A) Schematic depicting CREB and IRF competitive binding for CBP/p300 transcriptional coactivators, based on published literature (28, 29, 32, 33). (B) Representative Western blot analysis of CREB signaling induction with infection of WT and Hpse-KO cells. (C) Confocal immunofluorescence microscopy of WT and Hpse-KO cells showing CREB upregulation in infected WT cells. Scale bar: 100 μm. (D) Representative Western blot analysis of β-catenin signaling induction with infection of WT and Hpse-KO cells. (E) Confocal immunofluorescence microscopy of WT and Hpse-KO cells showing EGR1 cellular localization and GFP–HSV-1. Scale bar: 20 μm. (F) Top: Representative immunofluorescence micrographs of human corneal epithelial cells infected with GFP–HSV-1 and then incubated with specified inhibitors at 2 hours after GFP–HSV-1 infection; images captured at 24 hpi. Scale bar: 100 μm. Bottom: Schematic depicting known mechanisms of action of selected inhibitors. (G) Viral titers obtained from human corneal epithelial cells after incubation of specified inhibitors at the following concentrations from left to right: 12.5, 25, 50, and 100 µM (666-15 was used at concentrations of 5, 10, 15, and 20 μM due to unacceptable toxicity at higher levels). Significance determined by 2-way ANOVA with Dunnett’s correction for multiple comparisons against control (DMSO) at respective concentrations (n = 3). (H) Model of HPSE function at the interface of innate defense responses and cell survival. Infection and other cellular insults trigger activation of multiple prosurvival factors, including CREB, Akt, NF-κB, and β-catenin. Previous work and this study show that HPSE modulates nuclear trafficking of these transcription factors (TFs), which drive cellular proliferation, microbial replication, and carcinogenesis. Here, we show that HPSE inhibits type I IFN production and induction of necroptosis. These innate stress responses likely act to protect multicellular tissues from viral or cancerous spread by preventing uncontrolled cellular proliferation.