ChemBio Spotlight #2
Paper: Polysialylation Controls Dendritic Cell Trafficking by Regulation Chemokine Recognition
Polysialic acid (PolySia) has been shown to foster cancer progression and metastasis, but no mechanism has been elucidated. PolySia is a monosaccharide that is added post-transnationally to N/O linked glycan’s through the action of enzymes, ST8IV/II. It is also known to regulate the control of cell-cell and cell-matrix interactions controlling neuronal development and has been preliminarily shown to effect immune function. Recently, Kiermaier et al. (Science 2016;351:186-190) have tied these loose ends together showing how PolySia controls dendritic trafficking through chemokine regulation.
PolySia deficient mice display reduced cellularity of lymph nodes (LN) and a reduced LN mediated inflammatory response indicating a role for PolySia in regulating trafficking to LN’s. Immunoprecipitation reveled PolySia was present only on the surface of Dendritic Cells (DC), the antigen presenting immune cells. Further trafficking studies reveled PolySia -/- DC’s fail to migrate into the LN, even when injected into PolySia capable mice, indicating that the phenotype was cell autonomous.
Normally, CCR7 binds to chemokine’s (CCL19 or CCL21) to traffic DC’s into LN’s, however, in PolySia -/- conditions DC’s only respond to CCL19 activation not CCL21. Since CCL21 contains a known glycan binding, unstructured positive C-terminus domain it was likely that this was binding the negative PolySia. However, upon immunoprecipitation in both human and mouse cells it was determined that only CCR7 was polysialylated through both N/O type linkages not CCL21. NMR shift analysis then revealed that the CCL21 C-terminus acts in an auto-inhibitory manner inactivating its own chemokine domain, which is released by PolySia bound CCR7. This novel model of glycosylation-mediated release of chemokine auto-inhibition may also apply to other chemokine’s with similar c-terminus domains. In addition, since CCR7 is known to promote tumor metastasis this may explain the similar relationship observed with PolySia and its role in cancer progression and metasisis.
PolySia deficient DC’s fail to migrate in response to CCL21 signaling (bottom right).
Response to CCL19 signaling is intact (top right).