Sulfotransferase and Heparanase: Remodeling Engines in Promoting Virus Infection and Disease Development

Abstract

An extraordinary binding site generated in heparan sulfate (HS) structures, during its biosynthesis, provides a unique opportunity to interact with multiple protein ligands including viral proteins, and therefore adds tremendous value to this master molecule. An example of such a moiety is the sulfation at the C3 position of glucosamine residues in HS chain via 3-O sulfotransferase (3-OST) enzymes, which generates a unique virus-cell fusion receptor during herpes simplex virus (HSV) entry and spread. Emerging evidence now suggests that the unique patterns in HS sulfation assist multiple viruses in invading host cells at various steps of their life cycles. In addition, sulfated-HS structures are known to assist in invading host defense mechanisms and initiating multiple inflammatory processes; a critical event in the disease development. All these processes are detrimental for the host and therefore raise the question of how HS-sulfation is regulated. Epigenetic modulations have been shown to be implicated in these reactions during HSV infection as well as in HS modifying enzyme sulfotransferases, and therefore pose a critical component in answering it. Interestingly, heparanase (HPSE) activity is shown to be upregulated during virus infection and multiple other diseases assisting in virus replication to promote cell and tissue damage. These phenomena suggest that sulfotransferases and HPSE serve as key players in extracellular matrix remodeling and possibly generating unique signatures in a given disease. Therefore, identifying the epigenetic regulation of OST genes, and HPSE resulting in altered yet specific sulfation patterns in HS chain during virus infection, will be a significant a step toward developing potential diagnostic markers and designing novel therapies.

Keywords: heparan mimetic; heparan sulfate; heparanse; herpes simplex virus; sulfotranferases; viral entry.

Figure 1

The detrimental effects of heparan sulfate (HS) and modified-forms of HS in various pathological events ranging from supporting virus invasions into host cell, multiple cancers, and disease development.

Figure 2

The O-sulfation in HS chain is known to generate binding sites for multiple viral proteins to facilitate viral entry. For instance, sulfation at 3-O position on glucosamine residues generates a HSV-1 glycoprotein D (gD) receptor for entry. In addition, 3-O sulfation in HS facilitates the spread of cytomegalovirus (CMV). Similarly, 6-O sulfation in HS chain promotes hepatitis C and coxackievirus entry. Interestingly, it has been demonstrated that HIV glycoprotein gp120 interacts with 2-O sulfated HS during cell entry.

Figure 3

Multiple ways to demonstrate the significance of heparan sulfate (HS) in viral entry. (A) Moieties of HS chain provide initial docking sites for viral attachment, while sulfated HS chains generate receptors to promote virus-cell fusion. In contrast, the loss of HS may result in significant reduction of viral entry. For instance, (B) previous viral infection may result in resistance for incoming virus due to loss of HS. (C) In addition, enzymatic treatment of cells with heparanase may remove the critical moieties in HS chains required for viral entry and therefore results loss of viral infection. (D) Sequestering HS chain from the cell surface upon expressing viral protein renders resistance to in coming virus. (E) A competitive inhibition of viral entry by usage of HS mimetic on cell surface.

Figure 4

Emerging roles of heparanase (HPSE) and heparan sulfate (HS) modifying O-sulfotransferases (OSTs) in contributing directly in the onset of several disease pathologies. (A) An upregulation of HPSE under stress conditions such as low-pH, hypoxia, microbial infections, and inflammation degrades the normal architecture and basement membranes resulting the shedding of HSPG, cytokines/chemokines/growth factors (GFs) in ECM to initiate the cascade of inflammatory process. (B) Epigenetic regulations (hypo-methylation or hyper-methylation) of HS-modifying enzymes (2-, 6-, and 3-OSTs) resulting in either lower or over-expression of OST genes are widely documented in multiple diseases including cancer progression and certain invasive cancer phenotypes.