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Proximity Proteome Analysis Reveals Novel TREM2 Interactors in the ER-Mitochondria Interface of Human Microglia
Abstract:
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, 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.
Insights
Triggering receptor expressed on myeloid cells 2 (TREM2) is crucial in Alzheimer's disease (AD). New research reveals TREM2 interacts with proteins at Mitochondria-ER contact sites, impacting microglial function and AD pathology.
Area of Science:
- Neuroscience
- Cell Biology
- Biochemistry
Background:
- Triggering receptor expressed on myeloid cells 2 (TREM2) is vital for microglial function and Alzheimer's disease (AD) pathogenesis.
- Understanding TREM2's cellular interactors beyond DAP12 is crucial for elucidating its role in AD.
Approach:
- Utilized proximity labeling with TurboID to map protein-protein interactions of TREM2 in live mammalian cells.
- Investigated TREM2 interactome in human induced pluripotent stem cell-derived microglia.
Key Points:
- Identified novel TREM2-proximal proteins, including those at Mitochondria-ER contact sites (MERCs).
- Discovered TREM2 deficiency alters MERC thickness, a key metabolic structural parameter in microglia.
- Suggests novel roles for TREM2 in the structural plasticity of MERCs.
Conclusions:
- TREM2 is involved in regulating MERC structure and function.
- Dysregulation of MERC-related TREM2 functions may contribute to Alzheimer's disease pathobiology.
- This study provides new insights into TREM2's multifaceted role in cellular physiology and neurodegeneration.
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