Disease‐Associated Mutations of TREM2 Alter the Processing of N‐Linked Oligosaccharides in the Golgi Apparatus

Abstract

The triggering receptor expressed on myeloid cells 2 (TREM2) is an immune-modulatory receptor involved in phagocytosis and inflammation. Mutations of Q33X, Y38C and T66M cause Nasu-Hakola disease (NHD) which is characterized by early onset of dementia and bone cysts. A recent, genome-wide association study also revealed that single nucleotide polymorphism of TREM2, such as R47H, increased the risk of Alzheimer's disease (AD) similar to ApoE4. However, how these mutations affect the trafficking of TREM2, which may affect the normal functions of TREM2, was not known. In this study, we show that TREM2 with NHD mutations are impaired in the glycosylation with complex oligosaccharides in the Golgi apparatus, in the trafficking to plasma membrane and further processing by γ-secretase. Although R47H mutation in AD affected the glycosylation and normal trafficking of TREM2 less, the detailed pattern of glycosylated TREM2 differs from that of the wild type, thus suggesting that precise regulation of TREM2 glycosylation is impaired when arginine at 47 is mutated to histidine. Our results suggest that the impaired glycosylation and trafficking of TREM2 from endoplasmic reticulum/Golgi to plasma membrane by mutations may inhibit its normal functions in the plasma membrane, which may contribute to the disease.

The Triggering Receptor Expressed on Myeloid Cells 2 Binds Apolipoprotein E

“…rs75932628 causes an R47H missense mutation in the TREM2 ectodomain. Although the impact of this mutation is not completely understood, it appears to result in aberrant glycosylation and trafficking of the protein and impairs its ability to recognize plastic-immobilized lipids (20,21).…”

The Triggering Receptor Expressed on Myeloid Cells 2: A Molecular Link of Neuroinflammation and Neurodegenerative Diseases

“…Mutations in other downstream signaling components or other receptors that associate with DAP12 have not been identified. The homozygous or compound FTD-and NHD-associated mutations Y38C and T66M strongly impair the transport of TREM2 from the ER to the Golgi, and thus, its glycosylation and expression at the cell surface, also supporting a loss-of-function mechanism (25,26). These mutations also showed decreased solubility, accumulation in the ER, and induced ER stress (25).…”

“…The homozygous or compound FTD-and NHD-associated mutations Y38C and T66M strongly impair the transport of TREM2 from the ER to the Golgi, and thus, its glycosylation and expression at the cell surface, also supporting a loss-of-function mechanism (25,26). These mutations also showed decreased solubility, accumulation in the ER, and induced ER stress (25). Thus, TREM2 mutations might not only impair receptor signaling activity, but also cause cellular stress and thereby affect cell function and viability.…”

“…During biosynthesis and secretory transport, TREM2 also undergoes maturation by complex glycosylation (24,25,26), but the biological relevance of these modifications remains to be determined. TREM2 is also subjected to sequential proteolytic processing by ectodomain shedding and intramembranous cleavage (24,25,26) (Fig.…”

“…TREM2 is also subjected to sequential proteolytic processing by ectodomain shedding and intramembranous cleavage (24,25,26) (Fig. 2).…”