Chitinase-3-like protein 1 decodes chitosan acetylation patterns into toll-like receptor 2 signaling through heparan sulfate

Grossdorf, A.; Nabil, S.; Imelmann, C.; Hellmann, M.; Froese, J.; Awaad, E.; Tran, T.; Cord-Landwehr, S.; Raehse, N.; Kurc, O.; Yang, F.; Chen, H.; Gout, E.; Rosca, G.; Kusche-Gullberg, M.; Delbianco, M.; Cramer, J.; Gohlke, H.; Vives, R.; Weber, A.; Merzendorfer, H.; Osorio-Madrazo, A.; Grobe, K.; Moerschbacher, B.; Gorzelanny, C.

doi:10.64898/2026.06.15.732264

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bioRxiv · 10.64898/2026.06.15.732264

Chitinase-3-like protein 1 decodes chitosan acetylation patterns into toll-like receptor 2 signaling through heparan sulfate

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Abstract

Chitinase-3-like protein 1 (CHI3L1), which is associated with a wide range of inflammatory diseases, lacks chitinase activity but retains the ability to bind chitin and chitosan. Chitin is a major component of fungal cell walls, whereas chitosan is used in biomedicine. In addition to chitosan, CHI3L1 has been proposed to interact with heparan sulfate (HS), a highly sulfated glycosaminoglycan on mammalian cell surfaces. Here, we investigated how interactions with chitosan and HS regulate the pro-inflammatory activity of CHI3L1. Mapping of the chitin-binding cleft revealed preferential binding of CHI3L1 to chitosans with a regular acetylation pattern that, together with CHI3L1, promoted toll-like receptor 2 signaling. We further identified a dominant HS-binding site that recognizes a distinct HS sulfation code containing a coherent motif of N- and 6-O-sulfations. Mutation of this HS-binding site or impaired HS biosynthesis prevented CHI3L1 accumulation at the cell surface and abolished CHI3L1-mediated cell activation. Together, our findings establish HS as a critical co-receptor for CHI3L1 and reveal a pro-inflammatory cross-talk between HS, CHI3L1, and chitosan that may contribute to host defense against fungal pathogens and responses to chitosan-based biomaterials. These findings identify HS- and chitosan-dependent CHI3L1 signaling as a potential target for modulating inflammatory responses.

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Grossdorf, A., Nabil, S., Imelmann, C., Hellmann, M., Froese, J., Awaad, E., Tran, T., Cord-Landwehr, S., Raehse, N., Kurc, O., Yang, F., Chen, H., Gout, E., Rosca, G., Kusche-Gullberg, M., Delbianco, M., Cramer, J., Gohlke, H., Vives, R., Weber, A., Merzendorfer, H., Osorio-Madrazo, A., Grobe, K., Moerschbacher, B., Gorzelanny, C.. 2026-06-16. Chitinase-3-like protein 1 decodes chitosan acetylation patterns into toll-like receptor 2 signaling through heparan sulfate. https://doi.org/10.64898/2026.06.15.732264

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