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Neurodegeneration-associated mutant TREM2 proteins abortively cycle between the ER and ER-Golgi intermediate

Daniel W Sirkis1, Renan E Aparicio1, Randy Schekman2

  • 1Department of Molecular and Cell Biology, Howard Hughes Medical Institute, University of California, Berkeley, Berkeley, CA 94720.

Molecular Biology of the Cell
|August 4, 2017
PubMed

Insights

Mutant Triggering Receptor Expressed on Myeloid Cells 2 (TREM2) proteins are efficiently exported from the ER but fail to mature. These findings highlight the ER-Golgi Intermediate Compartment

Area of Science:

  • Neuroscience
  • Cell Biology
  • Genetics

Background:

  • Triggering Receptor Expressed on Myeloid Cells 2 (TREM2) is crucial for microglial function in the brain.
  • Rare homozygous mutations in TREM2 lead to early-onset neurodegeneration.
  • Understanding the intracellular trafficking of TREM2 is key to deciphering disease mechanisms.

Purpose of the Study:

  • To investigate how pathogenic TREM2 mutations affect its intracellular transport and maturation.
  • To determine the specific cellular compartments involved in TREM2 misprocessing.
  • To elucidate the role of the ER-Golgi Intermediate Compartment (ERGIC) in protein quality control.

Main Methods:

  • Cell-free coat protein complex II (COPII) vesicle budding assays to assess ER export.
  • Endoglycosidase D sensitivity assays to track protein maturation.
  • Lectin binding assays to identify post-ER compartments.
  • Gene silencing (depletion of COPI) to study ERGIC accumulation.

Main Results:

  • Most pathogenic TREM2 mutants show reduced cell-surface expression and impaired Golgi maturation.
  • Mutant TREM2 is efficiently exported from the endoplasmic reticulum (ER).
  • Mutant TREM2 accumulates in the ERGIC when COPI-dependent retrograde transport is inhibited.

Conclusions:

  • Efficient ER export is insufficient for normal cell-surface expression of TREM2.
  • The ERGIC functions as a critical quality control checkpoint for mutant membrane proteins.
  • These findings offer new insights into the pathogenesis of TREM2-associated neurodegenerative diseases.

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