The TREM-receptor family interactome in the human brain

The Triggering Receptors Expressed on Myeloid cells (TREMs) are a family of cell-surface receptors instrumental in the activation of different myeloid cells. TREM2, its most studied member, is genetically linked to Alzheimer disease (AD), and its interactions with BAmyloid; and APOE have placed it at the forefront of microglia dysfunction in the brain. However, the ligands and binding partners of the other TREM members (TREM1, TREML1, TREML2 and TREML4) are less well defined. Here, we used human AD and non-AD brain lysate to profile the interactome of the ligand binding domains of the different TREM receptors. Besides identifying known ligands for TREM1 (PGLYRP1), TREM2 (C1QL3, LGALSL) and TREML1 (Fibrinogens), we identified complement components and the apolipoproteins APOA1 and APOA4 as novel interactors of TREML1, and heparan sulfate modified proteins as binding partners for TREML2. Furthermore, similar to TREM2, all the TREMLs interacted with the apolipoproteins APOE and Clusterin. Using in vitro pulldowns with heparin, we confirmed that specifically TREML2 interacted with heparan sulfates, in a manner unaffected by the AD-linked S144G mutation. Together, our proteomics approach identified novel interactors for TREML1 and TREML2, cementing the role of the different TREM-proteins in lipid trafficking and immunity.