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.

3-O-sulfated heparan sulfate interactors target synaptic adhesion molecules from neonatal mouse brain and inhibit neural activity and synaptogenesis in vitro

“…We achieved this by using peptides which inhibit HSV-1 cell entry by interacting with non-3-O-sulfated HSs (peptide G1) or gD-type 3S-HSs (peptide G2) 26 . Several of our observations www.nature.com/scientificreports/ support the previously established specificity of these peptides 18,26,28,30 and thus the relevance of using them to target HSs. First, the recovery by pull-down assay of several HSPG and HBPs from the synaptosome surface are consistent with the capacity of G peptides to interact with cell surface HSs 26,30 .…”

“…Alternatively, studies on HSV-1 lifecycle may provide specific clues and tools to get insights on the 3S-HSs interactome and signalosome in the nervous system. HSPG are required for HSV-1 cell attachment and Hs3sts and their product 3S-HSs mediate HSV-1 cell entry through the viral protein gD 15,18,20,26 . Strikingly, recent data support the hypothesis that HSV-1 may contribute to the onset of AD by inducing the accumulation of amyloid Aß peptides and of hyperphosphorylated Tau, two hallmarks of AD degeneration in the brain 27 .…”

Inhibition of Human Cytomegalovirus Entry into Host Cells through A Pleiotropic Small Molecule

“…This work demonstrates for the first time the concept that small synthetic sulfated agents could effectively inhibit HCMV entry into host cells. Although previous work has demonstrated the concept that certain sulfated, natural, or unnatural polysaccharides (e.g., dextran sulfate, pentosan polysulfate, heparin, copolymers of acrylic acid) can inhibit HCMV infectivity in CHO-K1 and MRC-5 cells [71], the foundation for this activity was based on mimicking the polymeric scaffold of heparan sulfate, which has now been shown to be critical for HCMV entry [72][73][74][75]. In fact, the plausible molecular basis for this competitive inhibition was the interaction of sulfated polymers to viral glycoprotein gB of HCMV [25][26][27].…”

Preferential recognition and antagonism of SARS-CoV-2 spike glycoprotein binding to 3-O-sulfated heparan sulfate

“…It is important to note that the activity of HSPG modifying enzymes, e.g., 3OSTs, is dependent on the availability of optimal substrate sites within existing HS chains ( 15 , 16 , 52 ). In fact, the activity of the cascade of sulfotransferases and their isoforms (NDST, 2OST and 6OST), would determine the generation of 3- O -sulfated microdomains.…”