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bioRxiv · 10.1101/2023.03.21.533722

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

Kwak, C.·Finan, G. M.·Park, Y. R.·Mun, J. Y.·Rhee, H.-W.·Kim, T.-W.
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Abstract

Triggering receptor expressed on myeloid cells 2 (TREM2) plays a central role in microglial biology and the pathogenesis of Alzheimers 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, for mapping protein-protein interactions in live mammalian cells. We discovered novel TREM2-proximal proteins with diverse functions, including those localized to the Mitochondria-ER contact sites (MERCs), a dynamic subcellular hub implicated in a number of crucial cell physiology such as lipid metabolism. 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 structural plasticity of the MERCs, raising the possibility that dysregulation of MERC-related TREM2 functions contribute to AD pathobiology.

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Kwak, C., Finan, G. M., Park, Y. R., Mun, J. Y., Rhee, H.-W., Kim, T.-W.. 2023-03-24. Spatial Proteomics Reveals Novel TREM2 Interactors in ER-Mitochondria Interface in Microglia. https://doi.org/10.1101/2023.03.21.533722

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