Acidosis Increases MHC Class II–Restricted Presentation of a Protein Endowed with a pH-Dependent Heparan Sulfate–Binding Ability

Abstract

Heparan sulfate proteoglycans (HSPGs) are ubiquitously expressed molecules that participate in numerous biological processes. We previously showed that HSPGs expressed on the surface of APCs can serve as receptors for a hybrid protein containing an HS ligand and an Ag, which leads to more efficient stimulation of Th cells. To investigate whether such behavior is shared by proteins with inherent HS-binding ability, we looked for proteins endowed with this characteristic. We found that diphtheria toxin and its nontoxic mutant, called CRM197, can interact with HS. However, we observed that their binding ability is higher at pH 6 than at pH 7.4. Therefore, as extracellular acidosis occurs during infection by various micro-organisms, we assessed whether HS-binding capacity affects MHC class II–restricted presentation at different pHs. We first observed that pH decrease allows CRM197 binding to HSPG-expressing cells, including APCs. Then, we showed that this interaction enhances Ag uptake and presentation to Th cells. Lastly, we observed that pH decrease does not affect processing and presentation abilities of the APCs. Our findings show that acidic pH causes an HSPG-mediated uptake and an enhancement of T cell stimulation of Ags with the inherent ability to bind HSPGs pH-dependently. Furthermore, they suggest that proteins from micro-organisms with this binding characteristic might be supported more efficiently by the adaptive immune system when acidosis is triggered during infection.

Heparan Sulfate Proteoglycans Promote Telomerase Internalization and MHC Class II Presentation on Dendritic Cells

“…Interestingly, ionic and hydrophobic interactions appeared at pH ∼6.5, favoring stronger hTERT/HSPG interactions theoretically. These results confirm and reinforce the existence of positive correlation between acidosis and MHC-II-restricted Ag presentation already described by Léonetti and colleagues (41). Nevertheless, as producing full-length hTERT without any tag is still challenging, we could only use MBP-hTERT fusion protein.…”

pH-dependent and dynamic interactions of cystatin C with heparan sulfate

“…In fact, histidine-rich glycoprotein protein, which contains two cystatin-like domains, has been shown to bind HS in an acidic pH-dependent manner 21,22 . Other examples include selenoprotein P 23 , serum amyloid A 24 , diphtheria toxin 25 , and gp64 26 . Interestingly, a critical role of histidine residues has been demonstrated in acid pH-dependent HS binding of histidine-rich glycoprotein protein, selenoprotein P and amyloid A, which strongly suggests that incorporating histidines into the HS-binding sites is likely a universal mechanism for pH-dependent HS binding.…”

Heparan Sulfate Proteoglycans in Viral Infection and Treatment: A Special Focus on SARS-CoV-2

“…The therapeutics listed in Table 3 are FDA-approved drugs for the treatment of diseases other than SARS-CoV-2 infection, although an antiviral activity has been established for most of them [ 179 , 180 , 181 , 182 , 183 , 184 , 185 , 186 , 187 , 188 , 189 , 190 , 191 , 192 , 193 , 194 , 195 , 196 , 197 , 198 , 199 , 200 , 201 , 202 , 203 , 204 , 205 , 206 , 207 , 208 , 209 , 210 ].…”