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

doi:10.1172/jci.insight.144255

¹Department of Ophthalmology and Visual Sciences, University of Illinois at Chicago, Chicago, United States of America

²Department of Microbiology and Immunology, University of Illinois at Chicago, Chicago, United States of America

³Department of Dermatology, Northwestern University, Chicago, United States of America

⁴Department of Psychiatry, University of Illinois at Chicago, Chicago, United States of America

⁵Department of Pharmacology, University of California San Diego, La Jolla, United States of America

⁶Rappaport Faculty of Medicine, Haifa, Israel

⁷Department of Medical Biochemistry and Microbiology, University of Uppsala, Uppsala, Sweden

⁸Department of Medicine, University of Illinois at Chicago, Chicago, United States of America

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¹Department of Ophthalmology and Visual Sciences, University of Illinois at Chicago, Chicago, United States of America

²Department of Microbiology and Immunology, University of Illinois at Chicago, Chicago, United States of America

³Department of Dermatology, Northwestern University, Chicago, United States of America

⁴Department of Psychiatry, University of Illinois at Chicago, Chicago, United States of America

⁵Department of Pharmacology, University of California San Diego, La Jolla, United States of America

⁶Rappaport Faculty of Medicine, Haifa, Israel

⁷Department of Medical Biochemistry and Microbiology, University of Uppsala, Uppsala, Sweden

⁸Department of Medicine, University of Illinois at Chicago, Chicago, United States of America

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¹Department of Ophthalmology and Visual Sciences, University of Illinois at Chicago, Chicago, United States of America

²Department of Microbiology and Immunology, University of Illinois at Chicago, Chicago, United States of America

³Department of Dermatology, Northwestern University, Chicago, United States of America

⁴Department of Psychiatry, University of Illinois at Chicago, Chicago, United States of America

⁵Department of Pharmacology, University of California San Diego, La Jolla, United States of America

⁶Rappaport Faculty of Medicine, Haifa, Israel

⁷Department of Medical Biochemistry and Microbiology, University of Uppsala, Uppsala, Sweden

⁸Department of Medicine, University of Illinois at Chicago, Chicago, United States of America

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¹Department of Ophthalmology and Visual Sciences, University of Illinois at Chicago, Chicago, United States of America

²Department of Microbiology and Immunology, University of Illinois at Chicago, Chicago, United States of America

³Department of Dermatology, Northwestern University, Chicago, United States of America

⁴Department of Psychiatry, University of Illinois at Chicago, Chicago, United States of America

⁵Department of Pharmacology, University of California San Diego, La Jolla, United States of America

⁶Rappaport Faculty of Medicine, Haifa, Israel

⁷Department of Medical Biochemistry and Microbiology, University of Uppsala, Uppsala, Sweden

⁸Department of Medicine, University of Illinois at Chicago, Chicago, United States of America

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¹Department of Ophthalmology and Visual Sciences, University of Illinois at Chicago, Chicago, United States of America

²Department of Microbiology and Immunology, University of Illinois at Chicago, Chicago, United States of America

³Department of Dermatology, Northwestern University, Chicago, United States of America

⁴Department of Psychiatry, University of Illinois at Chicago, Chicago, United States of America

⁵Department of Pharmacology, University of California San Diego, La Jolla, United States of America

⁶Rappaport Faculty of Medicine, Haifa, Israel

⁷Department of Medical Biochemistry and Microbiology, University of Uppsala, Uppsala, Sweden

⁸Department of Medicine, University of Illinois at Chicago, Chicago, United States of America

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¹Department of Ophthalmology and Visual Sciences, University of Illinois at Chicago, Chicago, United States of America

²Department of Microbiology and Immunology, University of Illinois at Chicago, Chicago, United States of America

³Department of Dermatology, Northwestern University, Chicago, United States of America

⁴Department of Psychiatry, University of Illinois at Chicago, Chicago, United States of America

⁵Department of Pharmacology, University of California San Diego, La Jolla, United States of America

⁶Rappaport Faculty of Medicine, Haifa, Israel

⁷Department of Medical Biochemistry and Microbiology, University of Uppsala, Uppsala, Sweden

⁸Department of Medicine, University of Illinois at Chicago, Chicago, United States of America

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¹Department of Ophthalmology and Visual Sciences, University of Illinois at Chicago, Chicago, United States of America

²Department of Microbiology and Immunology, University of Illinois at Chicago, Chicago, United States of America

³Department of Dermatology, Northwestern University, Chicago, United States of America

⁴Department of Psychiatry, University of Illinois at Chicago, Chicago, United States of America

⁵Department of Pharmacology, University of California San Diego, La Jolla, United States of America

⁶Rappaport Faculty of Medicine, Haifa, Israel

⁷Department of Medical Biochemistry and Microbiology, University of Uppsala, Uppsala, Sweden

⁸Department of Medicine, University of Illinois at Chicago, Chicago, United States of America

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¹Department of Ophthalmology and Visual Sciences, University of Illinois at Chicago, Chicago, United States of America

²Department of Microbiology and Immunology, University of Illinois at Chicago, Chicago, United States of America

³Department of Dermatology, Northwestern University, Chicago, United States of America

⁴Department of Psychiatry, University of Illinois at Chicago, Chicago, United States of America

⁵Department of Pharmacology, University of California San Diego, La Jolla, United States of America

⁶Rappaport Faculty of Medicine, Haifa, Israel

⁷Department of Medical Biochemistry and Microbiology, University of Uppsala, Uppsala, Sweden

⁸Department of Medicine, University of Illinois at Chicago, Chicago, United States of America

Find articles by Koujah, L. in: JCI | PubMed | Google Scholar

¹Department of Ophthalmology and Visual Sciences, University of Illinois at Chicago, Chicago, United States of America

²Department of Microbiology and Immunology, University of Illinois at Chicago, Chicago, United States of America

³Department of Dermatology, Northwestern University, Chicago, United States of America

⁴Department of Psychiatry, University of Illinois at Chicago, Chicago, United States of America

⁵Department of Pharmacology, University of California San Diego, La Jolla, United States of America

⁶Rappaport Faculty of Medicine, Haifa, Israel

⁷Department of Medical Biochemistry and Microbiology, University of Uppsala, Uppsala, Sweden

⁸Department of Medicine, University of Illinois at Chicago, Chicago, United States of America

Find articles by Patil, C. in: JCI | PubMed | Google Scholar |

¹Department of Ophthalmology and Visual Sciences, University of Illinois at Chicago, Chicago, United States of America

²Department of Microbiology and Immunology, University of Illinois at Chicago, Chicago, United States of America

³Department of Dermatology, Northwestern University, Chicago, United States of America

⁴Department of Psychiatry, University of Illinois at Chicago, Chicago, United States of America

⁵Department of Pharmacology, University of California San Diego, La Jolla, United States of America

⁶Rappaport Faculty of Medicine, Haifa, Israel

⁷Department of Medical Biochemistry and Microbiology, University of Uppsala, Uppsala, Sweden

⁸Department of Medicine, University of Illinois at Chicago, Chicago, United States of America

Find articles by Hadigal, S. in: JCI | PubMed | Google Scholar

¹Department of Ophthalmology and Visual Sciences, University of Illinois at Chicago, Chicago, United States of America

²Department of Microbiology and Immunology, University of Illinois at Chicago, Chicago, United States of America

³Department of Dermatology, Northwestern University, Chicago, United States of America

⁴Department of Psychiatry, University of Illinois at Chicago, Chicago, United States of America

⁵Department of Pharmacology, University of California San Diego, La Jolla, United States of America

⁶Rappaport Faculty of Medicine, Haifa, Israel

⁷Department of Medical Biochemistry and Microbiology, University of Uppsala, Uppsala, Sweden

⁸Department of Medicine, University of Illinois at Chicago, Chicago, United States of America

Find articles by Kyzar, E. in: JCI | PubMed | Google Scholar |

¹Department of Ophthalmology and Visual Sciences, University of Illinois at Chicago, Chicago, United States of America

²Department of Microbiology and Immunology, University of Illinois at Chicago, Chicago, United States of America

³Department of Dermatology, Northwestern University, Chicago, United States of America

⁴Department of Psychiatry, University of Illinois at Chicago, Chicago, United States of America

⁵Department of Pharmacology, University of California San Diego, La Jolla, United States of America

⁶Rappaport Faculty of Medicine, Haifa, Israel

⁷Department of Medical Biochemistry and Microbiology, University of Uppsala, Uppsala, Sweden

⁸Department of Medicine, University of Illinois at Chicago, Chicago, United States of America

Find articles by Campeau, A. in: JCI | PubMed | Google Scholar

¹Department of Ophthalmology and Visual Sciences, University of Illinois at Chicago, Chicago, United States of America

²Department of Microbiology and Immunology, University of Illinois at Chicago, Chicago, United States of America

³Department of Dermatology, Northwestern University, Chicago, United States of America

⁴Department of Psychiatry, University of Illinois at Chicago, Chicago, United States of America

⁵Department of Pharmacology, University of California San Diego, La Jolla, United States of America

⁶Rappaport Faculty of Medicine, Haifa, Israel

⁷Department of Medical Biochemistry and Microbiology, University of Uppsala, Uppsala, Sweden

⁸Department of Medicine, University of Illinois at Chicago, Chicago, United States of America

Find articles by Wozniak, J. in: JCI | PubMed | Google Scholar |

¹Department of Ophthalmology and Visual Sciences, University of Illinois at Chicago, Chicago, United States of America

²Department of Microbiology and Immunology, University of Illinois at Chicago, Chicago, United States of America

³Department of Dermatology, Northwestern University, Chicago, United States of America

⁴Department of Psychiatry, University of Illinois at Chicago, Chicago, United States of America

⁵Department of Pharmacology, University of California San Diego, La Jolla, United States of America

⁶Rappaport Faculty of Medicine, Haifa, Israel

⁷Department of Medical Biochemistry and Microbiology, University of Uppsala, Uppsala, Sweden

⁸Department of Medicine, University of Illinois at Chicago, Chicago, United States of America

Find articles by Gonzalez, D. in: JCI | PubMed | Google Scholar |

¹Department of Ophthalmology and Visual Sciences, University of Illinois at Chicago, Chicago, United States of America

²Department of Microbiology and Immunology, University of Illinois at Chicago, Chicago, United States of America

³Department of Dermatology, Northwestern University, Chicago, United States of America

⁴Department of Psychiatry, University of Illinois at Chicago, Chicago, United States of America

⁵Department of Pharmacology, University of California San Diego, La Jolla, United States of America

⁶Rappaport Faculty of Medicine, Haifa, Israel

⁷Department of Medical Biochemistry and Microbiology, University of Uppsala, Uppsala, Sweden

⁸Department of Medicine, University of Illinois at Chicago, Chicago, United States of America

Find articles by Vlodavsky, I. in: JCI | PubMed | Google Scholar

¹Department of Ophthalmology and Visual Sciences, University of Illinois at Chicago, Chicago, United States of America

²Department of Microbiology and Immunology, University of Illinois at Chicago, Chicago, United States of America

³Department of Dermatology, Northwestern University, Chicago, United States of America

⁴Department of Psychiatry, University of Illinois at Chicago, Chicago, United States of America

⁵Department of Pharmacology, University of California San Diego, La Jolla, United States of America

⁶Rappaport Faculty of Medicine, Haifa, Israel

⁷Department of Medical Biochemistry and Microbiology, University of Uppsala, Uppsala, Sweden

⁸Department of Medicine, University of Illinois at Chicago, Chicago, United States of America

Find articles by Li, J. in: JCI | PubMed | Google Scholar |

¹Department of Ophthalmology and Visual Sciences, University of Illinois at Chicago, Chicago, United States of America

²Department of Microbiology and Immunology, University of Illinois at Chicago, Chicago, United States of America

³Department of Dermatology, Northwestern University, Chicago, United States of America

⁴Department of Psychiatry, University of Illinois at Chicago, Chicago, United States of America

⁵Department of Pharmacology, University of California San Diego, La Jolla, United States of America

⁶Rappaport Faculty of Medicine, Haifa, Israel

⁷Department of Medical Biochemistry and Microbiology, University of Uppsala, Uppsala, Sweden

⁸Department of Medicine, University of Illinois at Chicago, Chicago, United States of America

Find articles by Perkins, D. in: JCI | PubMed | Google Scholar

¹Department of Ophthalmology and Visual Sciences, University of Illinois at Chicago, Chicago, United States of America

²Department of Microbiology and Immunology, University of Illinois at Chicago, Chicago, United States of America

³Department of Dermatology, Northwestern University, Chicago, United States of America

⁴Department of Psychiatry, University of Illinois at Chicago, Chicago, United States of America

⁵Department of Pharmacology, University of California San Diego, La Jolla, United States of America

⁶Rappaport Faculty of Medicine, Haifa, Israel

⁷Department of Medical Biochemistry and Microbiology, University of Uppsala, Uppsala, Sweden

⁸Department of Medicine, University of Illinois at Chicago, Chicago, United States of America

Find articles by Finn, P. in: JCI | PubMed | Google Scholar |

¹Department of Ophthalmology and Visual Sciences, University of Illinois at Chicago, Chicago, United States of America

²Department of Microbiology and Immunology, University of Illinois at Chicago, Chicago, United States of America

³Department of Dermatology, Northwestern University, Chicago, United States of America

⁴Department of Psychiatry, University of Illinois at Chicago, Chicago, United States of America

⁵Department of Pharmacology, University of California San Diego, La Jolla, United States of America

⁶Rappaport Faculty of Medicine, Haifa, Israel

⁷Department of Medical Biochemistry and Microbiology, University of Uppsala, Uppsala, Sweden

⁸Department of Medicine, University of Illinois at Chicago, Chicago, United States of America

Find articles by Shukla, D. in: JCI | PubMed | Google Scholar |

JCI Insight. https://doi.org/10.1172/jci.insight.144255.
Copyright © 2021, Agelidis et al. This work is licensed under the Creative Commons Attribution 4.0 International License. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.

Published February 23, 2021 - Version history

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 follow 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.

Disruption of innate defense responses by endoglycosidase HPSE promotes cell survival

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