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Assessment of Selective mRNA Translation in Mammalian Cells by Polysome Profiling
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Translational regulation and protein-coding capacity of the 5' untranslated region of human TREM2

Motoaki Yanaizu1,2, Haruka Adachi1, Makoto Araki3

  • 1Department of Bioinformatics and Molecular Neuropathology, Meiji Pharmaceutical University, 2-522-1, Noshio, Kiyose-shi, Tokyo, 204-8588, Japan.

Communications Biology
|June 8, 2023
PubMed

Insights

The 5' untranslated region (UTR) of TREM2 regulates its protein translation via an upstream start codon (uAUG). This mechanism, specific to humans and primates, impacts TREM2 expression and its role in diseases like Alzheimer's.

Area of Science:

  • Molecular Biology
  • Neuroscience
  • Cell Biology

Background:

  • TREM2 (triggering receptor expressed on myeloid cells 2) is a transmembrane receptor crucial for microglial and macrophage function.
  • Elevated TREM2 expression is linked to age-related diseases, including Alzheimer's disease (AD), but its translational regulation is poorly understood.
  • The 5' untranslated region (5'-UTR) of messenger RNAs (mRNAs) plays a significant role in controlling protein synthesis.

Purpose of the Study:

  • To investigate the role of the 5'-UTR of human TREM2 in regulating its protein translation.
  • To identify potential upstream regulatory elements within the TREM2 5'-UTR.
  • To understand how TREM2 translational control is affected by cellular conditions like amino acid starvation.

Main Methods:

  • Bioinformatic analysis to identify conserved and species-specific features in the TREM2 5'-UTR.
  • Reporter assays and Western blotting to assess TREM2 protein expression from constructs with and without the 5'-UTR.
  • Site-directed mutagenesis to investigate the function of the upstream start codon (uAUG).
  • Proteasomal degradation assays and experiments under amino acid starvation conditions.

Main Results:

  • A species-specific uAUG was identified in the 5'-UTR of human TREM2, absent in many other species.
  • The TREM2 5'-UTR, through the uAUG, represses the translation of the canonical TREM2 protein (dTREM2).
  • A shorter TREM2 isoform (uTREM2) initiated from the uAUG was detected but found to be rapidly degraded by proteasomes.
  • The 5'-UTR mediated the downregulation of dTREM2 expression during amino acid starvation.

Conclusions:

  • The 5'-UTR of human TREM2 plays a critical, species-specific role in regulating TREM2 protein translation.
  • The uAUG within the 5'-UTR acts as a key regulatory element, influencing both canonical TREM2 expression and the production of a short, unstable isoform.
  • This translational control mechanism contributes to TREM2 expression levels and may be relevant in the context of neurodegenerative diseases and cellular stress responses.

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