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3-O-Sulfation of Heparan Sulfate Enhances Tau Interaction and Cellular Uptake

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Zhao, Jing | Zhu, Yanan | Song, Xuehong | Xiao, Yuanyuan | Su, Guowei | Liu, Xinyue | Wang, Zhangjie | Xu, Yongmei | Liu, Jian | Eliezer, David | Ramlall, Trudy, F | Lippens, Guy | Gibson, James | Zhang, Fuming | Linhardt, Robert, J | Wang, Lianchun | Wang, Chunyu

Edité par CCSD ; Wiley-VCH Verlag -

International audience. Prion-like transcellular spreading of tau in Alz-heimersD isease (AD) is mediated by tau binding to cell surface heparan sulfate (HS). However,t he structural determinants for tau-HS interaction are not well understood. Microarraya nd SPR assays of structurally defined HS oligosaccharides showt hat ar are 3-O-sulfation (3-O-S) of HS significantly enhances tau binding. In Hs3st1 À/À (HS 3-O-sulfotransferase-1 knockout) cells,reduced 3-O-S levels of HS diminished both cell surface binding and internalization of tau. In ac ell culture,t he addition of a3-O-S HS 12-mer reduced both tau cell surface binding and cellular uptake.N MR titrations mapped 3-O-S binding sites to the microtubule binding repeat 2(R2) and proline-richregion 2(PRR2) of tau. Taui so nly the seventh protein currently knownt or ecognize HS 3-O-sulfation. Our work demonstrates that this rare 3-O-sulfation enhances tau-HS binding and likely the transcellular spread of tau, providing an ovel target for disease-modifying treatment of AD and other tauopathies.

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