Strukturelle und funktionelle Charakterisierung der Chemokin-verstärkenden Aktivität des Varicella Zoster Virus (VZV) Glykoproteins C
Zusammenfassung der Projektergebnisse
Overall, our results suggest that VZV SgC acts differently to HSV-2 SgG, another vCKBP that enhances chemokine activity, since we previously showed that this vCKBP increases binding of the chemokine to the cell membrane in the proximity of CXCR4 as well as CXCR4 clustering (22). Moreover, HSV-2 SgG also increased the localization of CXCR4 in GM3-rich lipid rafts, while VZV SgC did not seem to do this. Despite these differences, both SgC and HSV-2 gG2 enhanced the internalization of CXCL12, without affecting the level of CXCR4 on the plasma membrane. VZV SgC increased CXCR4 phosphorylation and seemed to reduce its degradation, probably leading to higher recycling of the receptor to the plasma membrane. This led to higher phosphorylation of Erk1/2, especially at early time points. Our experiments investigating the individual role of CXCR4 and ACKR3 suggested that CXCR4 is the main receptor involved, although ACKR3 may be required. This is supported by the presence of residual SgC activity in Jurkat cells lacking CXCR4 expression, by the higher internalization of ACKR3 in the presence of SgC and CXCL12 and by the inhibition of β-arrestin signalling. This will be followed up since the modulation of atypical chemokine receptors by vCKBP has not been investigated. Moreover, ACKR3 is associated with tumour progression and metastasis. Therefore, if SgC inhibits ACKR3 activity as our results suggest, this could have important therapeutic implications. Finally, we could show that SgC increases the expression of certain chemokines and ICAM-1 and that a VZV expressing gC spread more efficiently from epithelial cells to lymphocytes than a gC-deficient virus.
