Dissociation of DNA damage sensing by endoglycosidase HPSE
Alex Agelidis,
Rahul K. Suryawanshi,
Chandrashekhar D. Patil,
Anaamika Campeau,
David J. Gonzalez,
Deepak Shukla
Affiliations
Alex Agelidis
Department of Microbiology and Immunology, University of Illinois at Chicago, Chicago, IL 60612, USA; Department of Ophthalmology and Visual Sciences, University of Illinois at Chicago, Chicago, IL 60612, USA
Rahul K. Suryawanshi
Department of Ophthalmology and Visual Sciences, University of Illinois at Chicago, Chicago, IL 60612, USA
Chandrashekhar D. Patil
Department of Ophthalmology and Visual Sciences, University of Illinois at Chicago, Chicago, IL 60612, USA
Anaamika Campeau
Department of Pharmacology, University of California, San Diego, La Jolla, CA 92093, USA; Skaggs School of Pharmacy, University of California, San Diego, La Jolla, CA 92093, USA
David J. Gonzalez
Department of Pharmacology, University of California, San Diego, La Jolla, CA 92093, USA; Skaggs School of Pharmacy, University of California, San Diego, La Jolla, CA 92093, USA
Deepak Shukla
Department of Microbiology and Immunology, University of Illinois at Chicago, Chicago, IL 60612, USA; Department of Ophthalmology and Visual Sciences, University of Illinois at Chicago, Chicago, IL 60612, USA; Corresponding author
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.
