Department of Molecular Pharmacology and Physiology, University of South Florida Morsani College of Medicine, Tampa, Florida, USA.
Departments of Chemistry and Chemical Biology, Center for Biotechnology and Interdisciplinary Studies, Rensselaer Polytechnic Institute, Troy, New York, USA; Department of Biological Sciences, Rensselaer Polytechnic Institute, Troy, New York, USA.
J Biol Chem. 2024 Sep;300(9):107691. doi: 10.1016/j.jbc.2024.107691. Epub 2024 Aug 17.
The triggering receptor expressed on myeloid cells-2 (TREM2), a pivotal innate immune receptor, orchestrates functions such as inflammatory responses, phagocytosis, cell survival, and neuroprotection. TREM2 variants R47H and R62H have been associated with Alzheimer's disease, yet the underlying mechanisms remain elusive. Our previous research established that TREM2 binds to heparan sulfate (HS) and variants R47H and R62H exhibit reduced affinity for HS. Building upon this groundwork, our current study delves into the interplay between TREM2 and HS and its impact on microglial function. We confirm TREM2's binding to cell surface HS and demonstrate that TREM2 interacts with HS, forming HS-TREM2 binary complexes on microglia cell surfaces. Employing various biochemical techniques, including surface plasmon resonance, low molecular weight HS microarray screening, and serial HS mutant cell surface binding assays, we demonstrate TREM2's robust affinity for HS, and the effective binding requires a minimum HS size of approximately 10 saccharide units. Notably, TREM2 selectively binds specific HS structures, with 6-O-sulfation and, to a lesser extent, the iduronic acid residue playing crucial roles. N-sulfation and 2-O-sulfation are dispensable for this interaction. Furthermore, we reveal that 6-O-sulfation is essential for HS-TREM2 ternary complex formation on the microglial cell surface, and HS and its 6-O-sulfation are necessary for TREM2-mediated ApoE3 uptake in microglia. By delineating the interaction between HS and TREM2 on the microglial cell surface and demonstrating its role in facilitating TREM2-mediated ApoE uptake by microglia, our findings provide valuable insights that can inform targeted interventions for modulating microglial functions in Alzheimer's disease.
髓样细胞触发受体 2（TREM2）是一种关键的先天免疫受体，它协调炎症反应、吞噬作用、细胞存活和神经保护等功能。TREM2 的变体 R47H 和 R62H 与阿尔茨海默病有关，但潜在机制仍不清楚。我们之前的研究表明，TREM2 与肝素硫酸酯（HS）结合，并且变体 R47H 和 R62H 对 HS 的亲和力降低。在此基础上，我们目前的研究深入探讨了 TREM2 与 HS 之间的相互作用及其对小胶质细胞功能的影响。我们证实了 TREM2 与细胞表面 HS 的结合，并表明 TREM2 与 HS 相互作用，在小胶质细胞膜表面形成 HS-TREM2 二元复合物。我们利用各种生化技术，包括表面等离子体共振、低分子量 HS 微阵列筛选和连续 HS 突变细胞表面结合测定，证明了 TREM2 对 HS 的强大亲和力，并且有效结合需要大约 10 个糖单位的最小 HS 大小。值得注意的是，TREM2 选择性地结合特定的 HS 结构，6-O-硫酸化和程度较小的 iduronic 酸残基起着关键作用。N-硫酸化和 2-O-硫酸化对于这种相互作用是可有可无的。此外，我们揭示了 6-O-硫酸化对于 HS-TREM2 在小胶质细胞膜表面的三元复合物形成是必不可少的，并且 HS 和其 6-O-硫酸化对于 TREM2 介导的 ApoE3 在小胶质细胞中的摄取是必需的。通过描绘 HS 和 TREM2 在小胶质细胞膜表面的相互作用，并证明其在促进 TREM2 介导的 ApoE 摄取中的作用，我们的研究结果为靶向干预调节阿尔茨海默病中小胶质细胞功能提供了有价值的见解。
