Translational regulation and protein-coding capacity of the 5′ untranslated region of human TREM2

TREM2 is a transmembrane receptor expressed in microglia and macrophages. Elevated TREM2 levels in these cells are associated with age-related pathological conditions, including Alzheimer’s disease. However, the regulatory mechanism underlying the protein expression of TREM2 remains unclear. In this study, we uncover the role of the 5′ untranslated region (5′-UTR) of human TREM2 in translation. An upstream start codon (uAUG) in the 5′-UTR of TREM2 is specific to some primates, including humans. The expression of the conventional TREM2 protein, starting from the downstream AUG (dTREM2), is repressed by the 5′-UTR in a uAUG-mediated manner. We also detect a TREM2 protein isoform starting from uAUG (uTREM2) that is largely degraded by proteasomes. Finally, the 5′-UTR is essential for the downregulation of dTREM2 expression in response to amino acid starvation. Collectively, our study identifies a species-specific regulatory role of the 5′-UTR in TREM2 translation.