Heparanase, cell signaling, and viral infections

Abstract

Heparanase (HPSE) is a multifunctional protein endowed with many non-enzymatic functions and a unique enzymatic activity as an endo-β-d-glucuronidase. The latter allows it to serve as a key modulator of extracellular matrix (ECM) via a well-regulated cleavage of heparan sulfate side chains of proteoglycans at cell surfaces. The cleavage and associated changes at the ECM cause release of multiple signaling molecules with important cellular and pathological functions. New and emerging data suggest that both enzymatic as well as non-enzymatic functions of HPSE are important for health and illnesses including viral infections and virally induced cancers. This review summarizes recent findings on the roles of HPSE in activation, inhibition, or bioavailability of key signaling molecules such as AKT, VEGF, MAPK-ERK, and EGFR, which are known regulators of common viral infections in immune and non-immune cell types. Altogether, our review provides a unique overview of HPSE in cell-survival signaling pathways and how they relate to viral infections.

COVID‐19‐induced endotheliitis: emerging evidence and possible therapeutic strategies

“…32 It is often overexpressed during viral infections and act as a regulator of virus release after replication has occurred, promoting its dissemination. [71][72][73][74] Additionally, it may be upregulated by pro-inflammatory molecules such as IL-1 and TNF-a. Once activated, heparanase stimulates the expression and release of pro-inflammatory cytokines, including TNF-a, IL-1 and IL-6.…”

“…28 In contrast to heparin, DF also exhibits broader anticytokine, anti-inflammatory and endothelial-stabilising properties. Importantly, by acting on the heparanase-HS axis, 74,102 DF may limit viral infectivity given its capacity to i) compete with HS and thereby possibly inhibit virus-cell adhesion and entry, ii) inhibit heparanase enzymatic activity and thereby attenuate virus detachment/release and spread 74 and iii) inhibit heparanase-mediated activation of immune cells and thereby upregulation of pro-inflammatory cytokines and the associated self-sustaining systemic inflammatory host response (Fig 1). Actively accruing, international Phase II clinical trials are now underway and should shed critical light on DF's therapeutic potential in patients with COVID-19 (examples include clinicaltrials.gov; NCT04348383, NCT04335201).…”

Cathepsin L in COVID-19: From Pharmacological Evidences to Genetics

“…Furthermore, CatL activates heparanase and contributes to the inflammatory cascade by macrophage activation ( Garsen et al., 2016 ). Heparanase is an important factor that participates on viral infection processes ( Koganti et al., 2020 ).…”

Heparan Sulfate Proteoglycans Biosynthesis and Post Synthesis Mechanisms Combine Few Enzymes and Few Core Proteins to Generate Extensive Structural and Functional Diversity

“…Extracellular activity of heparanase leads to the loosening of ECM architecture and the release of biologically active HS fragments as well as ECM stored HS ligands such as growth factors, chemokines and morphogens. Based on its multiple activities, heparanase has been associated with a wide range of physiological and pathological processes, including tumor growth, angiogenesis, invasion and chemoresistance, inflammation, fibrosis, coagulation and thrombosis or viral infection [ 208 , 210 , 211 , 212 ]. Noteworthy, heparanase II (Hpa2), a homolog of heparanase, has been identified [ 213 ].…”