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Sulfation Revisited, DHEA and Syndecans

Earlier on these series of posts, Sulfation was discussed as being -potentially- important.  Several Algorithmic Runs identified Sulfation and associated Genes as being important, therefore Sulfation required extensive Research to understand its possible involvement (as suggested by Machine Learning).

In [1] we read :

"Sulfation is involved in a variety of biological processes, including detoxification, hormone regulation, molecular recognition, cell signaling, and viral entry into cells.[1] It is among the reactions in phase II drug metabolism, frequently effective in rendering a xenobiotic less active from a pharmacological and toxicological standpoint, but sometimes playing a role in the activation of xenobiotics (e.g. aromatic amines, methyl-substituted polycyclic aromatic hydrocarbons). Another example of biological sulfation is in the synthesis of sulfonated glycosaminoglycans, such as heparin, heparan sulfate, chondroitin sulfate, and dermatan sulfate. Sulfation is also a possible posttranslational modification of proteins"

Bile Acids (the importance of was discussed in previous posts) are transformed to a less toxic form through Sulfation [2].

The Wikipedia entry on Sulfation talks about Heparan sulfate which deserves a closer inspection :

 In [2] we read :

"The heparan sulfate chains due to their vast structural diversity are able to bind and interact with a wide variety of proteins, such as growth factors, chemokines, morphogens, extracellular matrix components, enzymes, among others. There is a specificity directing the interactions of heparan sulfates and target proteins, regarding both the fine structure of the polysaccharide chain as well precise protein motifs. Heparan sulfates play a role in cellular signaling either as receptor or co-receptor for different ligands, and the activation of downstream pathways is related to phosphorylation of different cytosolic proteins either directly or involving cytoskeleton interactions leading to gene regulation."
 We note that Heparan sulfates are associated with cytosolic proteins involving cytoskeleton interactions. (The importance of proper cytoskeleton functioning was discussed in previous posts).

Furthermore in [3] we read :

"Heparan sulfate proteoglycans (HSPGs) are glycoproteins, with the common characteristic of containing one or more covalently attached heparan sulfate (HS) chains, a type of glycosaminoglycan (GAG) (Esko et al. 2009). Cells elaborate a relatively small set of HSPGs (∼17) that fall into three groups according to their location: membrane HSPGs, such as syndecans and glycosylphosphatidylinositol-anchored proteoglycans (glypicans), the secreted extracellular matrix HSPGs (agrin, perlecan, type XVIII collagen), and the secretory vesicle proteoglycan, serglycin"

According to [4] Syndecan-2 (a subtype of Syndecans - Gene name SDC2 ) plays an important role for the actin cytoskeleton :

"Syndecans, a family of transmembrane heparan sulphate proteoglycans, contribute to various biological processes, including adhesion, motility, proliferation, differentiation and morphogenesis. We document here the involvement of syndecan-2 acting alone or co-operatively with integrin alpha5beta1, for regulation of actin-cytoskeletal organization on cell adhesion to fibronectin, using fibronectin-recombinant polypeptides containing the ligands for either or both of these receptors as substrata. "

We could then hypothesize that impaired Sulfation leads to impaired production of Heparan Sulfate ProteoGlycans which in turn affect Syndecans (and more importantly Syndecan-2 in our case).

However Sulfation has yet one more important role : Oxysterol Sulfation. In [5] we read :

"Oxysterol sulfation as a regulatory pathway has grown out of recent studies in the past seven years, including discovery of a novel oxysterol sulfate, identification of a key enzyme hydroxysterol sulfotransferase 2B1b (SULT2B1b) involved in oxysterol sulfate synthesis, and investigation into the role of oxysterol sulfates in regulation of lipid metabolism, inflammatory responses, and cell proliferation. Ten years ago, our laboratories began investigating the role of intracellular cholesterol transport proteins in the regulation of bile acid synthesis and cholesterol degradation (68, 75). We found that bile acid synthesis via the acidic, “alternative”, pathway was limited by mitochondrial cholesterol uptake. This barrier could be overcome by increasing expression of the intracellular cholesterol transporter StarD1 (68, 73, 75). This suggests a physiological role for StarD1. Increases in StarD1 expression also led to upregulation of biliary cholesterol secretion and downregulation of cholesterol, fatty acid, and triglyceride biosynthesis"

Gene  SULT2B1 (of which SULT2b1b is an isoform) is -interestingly- associated with LXR. More specifically in [5] we read :

"LXR signaling from proliferation, directly linking sterol homeostasis to the anti-proliferative action of LXR. Mice lacking LXRβ exhibit lymphoid hyperplasia and enhanced responses to antigenic challenge, indicating that proper regulation of LXR- dependent sterol metabolism is important for immune responses. These data implicate LXR signaling in a metabolic checkpoint that modulates cell proliferation and immunity"

but more importantly we see a connection of LXR Receptor and Sterol Metabolism to regulate T Cell function :

"Antigen-specific CD8+ T cells were enumerated ex vivo one week post immunization by intracellular IFN-γ and TNF-α staining after a short term in vitro restimulation with the E1B antigen E1B192-200 (VNIRNCCYI) (Toes et al., 1998). Remarkably, FACS analysis indicated that the frequency of antigen-specific Lxrβ null IFN-γ + (p=0.02) or TNFα+ (p=0.01) CD8+ T cells was 2–3 fold higher than their WT counterparts (Fig. 7C,D). Thus, antigen-driven expansion of CD8+ T cells is negatively regulated by LXRβ in WT mice. Taken together, these data establish LXR-dependent sterol metabolism as a novel signaling pathway regulating T cell function and immune responses."

In previous posts we discussed about the importance of CYP27A1. In [7] we read :

"The rate-limiting step controlling CYP27A1 activity is the flux of cholesterol from the outer to the inner mitochondrial membrane, via a mitochondrial cholesterol trafficking complex (discussed below). Mitochondrial oxysterols therefore act as key cell signalling molecules, the levels of which can be moderated by sulfation (SULT2B1b), esterification (ACAT-1) or metabolism to soluble bile acid derivatives "

So we have evidence of  SULT2b1b being of particular importance for further investigation. Note also that SULT2b1b is responsible for Cholesterol Sulfate production.

Moreover, SULT2A1 and SULT1E1 are responsible for sulfonation of DHEAS [6].  In [8] we find yet one more indirect association of Sulfation -because of DHEAS- with CD3+ and CD8+ T Cells :

"There were significant and positive correlations between serum DHEAS and serum zinc and the mitogen-induced expression of the CD69 molecule on CD3+CD8+ T cells (an indicator of early T cell activation). There was a significant and negative correlation between serum DHEAS and the increase in the serum alpha-2 protein fraction (an inflammatory marker). Serum IGF1, but not DHEAS, was significantly and inversely correlated to age. The results show that CFS is accompanied by lowered levels of DHEAS and that the latter may play a role in the immune (defect in the early activation of T cells) and the inflammatory pathophysiology of CFS"

Note that SULT2A1 sulfonates DHEA and Pregnenolone (among others), SULT2B1a sulfonates Pregnenolone and SULT2B1b is involved with Cholesterol Sulfonation [8]
The following Genes are proposed for further investigation : STS, SULT1A1, SULT2A1, SULT2B1, STARD1,SDC2

As discussed, Sulfation is a rather extensive subject with numerous implications which deserves a closer look in future posts.


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[2] :

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