Heparan Sulfate Modified with 6-<i>O</i>-sulfation Forms Functional Complexes with TREM2 on Microglia Cell Surface

Microglia are the brain-resident immune cells that maintain homeostasis via phagocytosis.Impairment of microglial function increases the risk of neurodegenerative diseases such as Alzheimer's disease (AD) [Gao et al. (2023) Signal Transduct Target Ther.8, 359].TREM2 is a receptor expressed on the surface of myeloid cells, including microglia, and is involved in inflammatory responses, phagocytosis, and cell proliferation via signal transduction [Hou et al. (2022) Mol.Neurodegener.17, 84].Previous structural studies on the TREM2 protein have revealed that amino acid mutations in TREM2 (R47H, R62H), known risk factors for AD, are exposed to the protein surface in the extracellular domain [Sudon et al. (2018) J. Biol.Chem.293, 12634-12646].Furthermore, it has been shown that TREM2 interacts with heparan sulfate (HS) on the cell surface, and this binding is reduced in R47H and R62H mutants [Kober et al. (2016) Elife 5, e20391].These findings highlighted the involvement of HS recognition of TREM2 in AD pathology.However, the HS structure recognized by TREM2 and the relationship between the HS structure and the cellular functions involved in AD remains unclear.Here, I introduce a report that provides insight into the HS structure recognized by TREM2 in microglial cells and the microglial functions regulated through TREM2 recognition by HS [McMillan et al. (2024) J. Biol.Chem.300, 107691].To elucidate the HS structure recognized by TREM2, the authors measured its binding affinity by surface plasmon resonance (SPR).The dissociation constant (Kd) between heparin, an HS analog, and TREM2 was 1.37 1.2010 -9 M. To investigate the minimum size of HS recognized by TREM2, the solution-competitive TREM2 binding SPR analysis was performed using heparinderived oligosaccharides of various sizes, ranging from dp4 to dp16.The interaction between heparin and TREM2 was barely inhibited by the oligosaccharide dp8, but approximately 45% and 93% inhibition was observed with dp10 and dp16, respectively.These findings indicate that the binding of HS to TREM2 requires a minimum heparin size of approximately ten saccharide units.Since HS contains various sulfation modifications, the authors also examined which modifications contribute to the interaction between HS and TREM2.N-Desulfated or 2-O-desulfated heparins had little effect on the interaction with TREM2, whereas 6-O-desulfated heparin displayed virtually no interaction with TREM2.This indicates that HS 6-O-sulfation is essential for the interaction with TREM2.Considering HS structural heterogeneity,