Spatial Proteomics Reveals Novel TREM2 Interactors in ER-Mitochondria Interface in Microglia

Triggering receptor expressed on myeloid cells 2 (TREM2) plays a central role in microglial biology and the pathogenesis of Alzheimer's disease (AD). Besides DNAX-activating protein 12 (DAP12), a communal adaptor for TREM2 and many other receptors, other cellular interactors of TREM2 remain largely elusive. We employed a proximity labeling approach using a biotin ligase, TurboID, and discovered novel TREM2-proximal proteins, many of which localized to the Mitochondria-ER contact sites (MERCs). TREM2 deficiency alters the thickness (inter-organelle distance) of MERCs, a structural parameter of metabolic state, in microglia derived from human induced pluripotent stem cells. Our TurboID-based TREM2 interactome study suggest novel roles for TREM2 in the regulation of MERCs, raising the possibility that dysregulation of MERC-related TREM2 functions contribute to AD pathobiology. ### Competing Interest Statement The authors have declared no competing interest.