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bioRxiv · 10.1101/364562

Host Enzymes Heparanase and Cathepsin L Promote Herpes Simplex Virus-2 Release from Cells

Hopkins, J.·Yadavalli, T.·Agelidis, A.·Shukla, D.
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Abstract

Herpes simplex virus-2 (HSV-2) can productively infect many different cell types of human and non-human origin. Here we demonstrate interconnected roles for two host enzymes, heparanase (HPSE) and cathepsin L in HSV-2 release from cells. In vaginal epithelial cells and other cell lines tested, HSV-2 causes heparan sulfate shedding and upregulation in HPSE levels during the productive phase of infection. We also noted increased levels of cathepsin L and show that regulation of HPSE by cathepsin L via cleavage of HPSE proenzyme is important for infection. Furthermore, inhibition of HPSE by a specific inhibitor, OGT 2115, dramatically reduces HSV-2 release from vaginal epithelial cells. Likewise, we show evidence that the inhibition of cathepsin L is detrimental to the infection. The HPSE increase after infection is mediated by an increased NF-{kappa}B nuclear localization and a resultant activation of HPSE transcription. Together these mechanisms contribute to the removal of heparan sulfate from the cell surface, and thus facilitate virus release from cells.\n\nImportanceGenital infections by HSV-2 represent one of the most common sexually transmitted viral infections. The virus causes painful lesions, and sores around the genitals or rectum. Intermittent release of the virus from infected tissues during sexual activities is the most common cause of transmission. At the molecular level, cell surface heparan sulfate (HS) is known to provide attachment sites for HSV-2. While the removal of HS during HSV-1 release has been shown, not much is known about the host factors and their regulators that contribute to HSV-2 release from natural target cell types. Here we suggest a role for the host enzyme heparanase in HSV-2 release. Our work reveals that in addition to the regulation of transcription by NF-{kappa}B, HPSE is also regulated post-translationally by cathepsin L and that inhibition of heparanase activity directly affects HSV-2 release. We provide unique insights into the host mechanisms controlling HSV-2 egress and spread.

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Hopkins, J., Yadavalli, T., Agelidis, A., Shukla, D.. 2018-07-08. Host Enzymes Heparanase and Cathepsin L Promote Herpes Simplex Virus-2 Release from Cells. https://doi.org/10.1101/364562

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