Article

Heparanase is a host enzyme required for herpes simplex virus-1 release from cells

  • Nature Communications volume 6, Article number: 6985 (2015)
  • doi:10.1038/ncomms7985
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Abstract

Herpesviruses exemplified by herpes simplex virus-1 (HSV-1) attach to cell surface heparan sulfate (HS) for entry into host cells. However, during a productive infection, the HS moieties on parent cells can trap newly exiting viral progenies and inhibit their release. Here we demonstrate that a HS-degrading enzyme of the host, heparanase (HPSE), is upregulated through NF-kB and translocated to the cell surface upon HSV-1 infection for the removal of HS to facilitate viral release. We also find a significant increase in HPSE release in vivo during infection of murine corneas and that knockdown of HPSE in vivo inhibits virus shedding. Overall, we propose that HPSE acts as a molecular switch for turning a virus-permissive ‘attachment mode’ of host cells to a virus-deterring ‘detachment mode’. Since many human viruses use HS as an attachment receptor, the HPSE-HS interplay may delineate a common mechanism for virus release.

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Acknowledgements

This work was supported by the National Institutes of Health grants AI081869 (D.S.), EY023058 (D.S.), AI103754 (D.S.) and CA138340 (R.D.S.), a core grant (EY001792), and unrestricted funds from Research to Prevent Blindness Inc. We thank Dr Patricia G. Spear (Northwestern University) for providing viruses used in this study. We are grateful to Dr Sandeep Jain and Dr Joy Sarkar (University of Illinois at Chicago) for providing their expertise with StereoLumar microscope. We thank Dr Israel Vlodavsky (Rappaport Institute) for providing HPSE mutant expression plasmids. HPSE luciferase constructs were a kind gift from Dr Xiulong Xu (Rush University). We also thank Dr Michael Karin (University of California, San Diego) for providing mut IkBa expression constructs, !and Dr Bernard Roizman (University of Chicago) and Dr Neal DeLuca (University of Pittsburgh) for access to several viral transcription factor expression constructs.

Author information

Author notes

    • Satvik R. Hadigal
    •  & Alex M. Agelidis

    These authors contributed equally to this work

Affiliations

  1. Ocular Virology Laboratory, Department of Ophthalmology and Visual Sciences, University of Illinois at Chicago, 1855 West Taylor Street, M/C 648, Chicago, Illinois 60612, USA

    • Satvik R. Hadigal
    • , Alex M. Agelidis
    • , Ghadah A. Karasneh
    • , Thessicar E. Antoine
    • , Abraam M. Yakoub
    • , Ali R. Djalilian
    •  & Deepak Shukla
  2. Department of Microbiology and Immunology, College of Medicine, University of Illinois at Chicago, E-704 Medical Sciences Building, M/C 790, 835 South Wolcott Avenue, Chicago, Illinois 60612, USA

    • Alex M. Agelidis
    • , Ghadah A. Karasneh
    • , Thessicar E. Antoine
    • , Abraam M. Yakoub
    •  & Deepak Shukla
  3. Department of Pathology, University of Alabama at Birmingham, 1720 2nd Avenue South, Birmingham, Alabama 35294, USA

    • Vishnu C. Ramani
    •  & Ralph D. Sanderson

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Contributions

D.S., S.R.H. and A.M.A. designed experiments; S.R.H., A.M.A., G.A.K., T.E.A., A.M.Y. and V.C.R. performed experiments and analysed data; S.R.H., A.M.A., D.S., R.D.S. and A.R.D. wrote the manuscript.

Competing interests

The authors declare no competing financial interests.

Corresponding author

Correspondence to Deepak Shukla.

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