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ResearchIn-Press PreviewCell biologyMicrobiology Open Access | 10.1172/jci.insight.144255

Disruption of innate defense responses by endoglycosidase HPSE promotes cell survival

Alex Agelidis,1 Benjamin A. Turturice,2 Rahul K. Suryawanshi,1 Tejabhiram Yadavalli,1 Dinesh Jaishankar,3 Joshua Ames,1 James Hopkins,1 Lulia Koujah,1 Chandrashekhar D. Patil,1 Satvik R. Hadigal,1 Evan J. Kyzar,4 Anaamika Campeau,5 Jacob M. Wozniak,5 David J. Gonzalez,5 Israel Vlodavsky,6 Jin-ping Li,7 David L. Perkins,8 Patricia W. Finn,8 and Deepak Shukla1

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 Agelidis, 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 Turturice, B. 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 Suryawanshi, R. 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 Yadavalli, T. 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 Jaishankar, 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 Ames, 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 Hopkins, 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 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 |

Published February 23, 2021 - More info

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
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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 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.

Graphical Abstract
graphical abstract
Supplemental material

View Dataset S1. Transcriptomics count matrices

View Dataset S2. Baseline transcriptomics differential expression

View Dataset S3. Results of clustered transcriptomics ClueGO gene ontology analysis

View Dataset S4. Results of baseline transcriptomics ClueGO gene ontology analysis

View Dataset S5. Quantitative proteomics normalized expression matrix

View

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