Dissociation of DNA damage sensing by endoglycosidase HPSE

Abstract

Summary Balance between cell proliferation and elimination is critical in handling threats both exogenous and of internal dysfunction. Recent work has implicated a conserved but poorly understood endoglycosidase heparanase (HPSE) in the restriction of innate defense responses, yet biochemical mediators of these key functions remained unclear. Here, an unbiased immunopurification proteomics strategy is employed to identify and rank uncharacterized interactions between HPSE and mediators of canonical signaling pathways linking cell cycle and stress responses. We demonstrate with models of genotoxic stress including herpes simplex virus infection and chemotherapeutic treatment that HPSE dampens innate responses to double-stranded DNA breakage by interfering with signal transduction between initial sensors and downstream mediators. Given the long-standing recognition of HPSE in driving late-stage inflammatory disease exemplified by tissue destruction and cancer metastasis, modulation of this protein with control over the DNA damage response imparts a unique strategy in the development of unconventional multivalent therapy.

Pathophysiology of reinfection by exogenous HSV-1 is driven by heparanase dysfunction

“…HPSE is up-regulated in a variety of diseases including virus infections ( 17 ). Similar to HSPGs, emerging evidence demonstrates the importance of HPSE in inflammatory reactions, particularly at immune privilege sites like the eye and central nervous system ( 16 , 18 , 24 , 25 ).…”

Extracellular matrix-based cancer targeting

“…Degradation of HS by HPSE contributes to ECM disassembly and hence facilitates cancer metastasis and inflammation. In addition, it affects diverse patho(physio)logical processes ranging from gene transcription to signal transduction, autophagy and DNA damage [73,74]. A key mechanism by which HPSE accomplishes its multiple effects on cells and tissues is by regulating the bioavailability of HS-bound growth factors, chemokines, and cytokines, priming the TME.…”

“…HPSE acting on HS chains of HSPGs creates a permissive environment for cell proliferation, activation and differentiation. Furthermore, HPSE is a key player in abundant pathologies including inflammation, autoimmunity, tissue fibrosis, kidney dysfunction, diabetes, viral infection and cancer [74,[77][78][79]. The development of HPSE inhibitors as anti-inflammatory and anti-cancer drugs is, therefore, a promising area for matrix-based pharmacological targeting [80].…”

Host Molecules That Promote Pathophysiology of Ocular Herpes

“…Its actions in the cell nucleus generate pro-inflammatory and pro-angiogenic conditions and help establish HPSE as a host virulence factor. In addition to directly promoting a toxic environment inside an HSV-1 infected cell, HPSE can also restrict cell-intrinsic defense mechanisms resulting in a hostile takeover of the host cell reprogramming by HSV-1 ( Agelidis et al, 2021a ). HPSE through its diverse yet well-regulated interactome can interfere with double-stranded DNA breakage response by blocking signal transduction between sensors and downstream mediators thereby reducing the cell’s ability to fight HSV-1 infection ( Agelidis et al, 2021b ).…”