The role of TREM2 N-glycans in trafficking to the cell surface and signal transduction of TREM2

Shirotani, Keiro; Hatta, Daisuke; Wakita, Naoki; Watanabe, Kaori; Iwata, Nobuhisa

doi:10.1093/jb/mvac073

Cited by 6 publications

(7 citation statements)

References 39 publications

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“…Taken together, the thermal denaturation study identified a critical role of N79 glycosylation on the thermal stability of TREM2. Interestingly, these two N glycans were shown to facilitate trafficking to the cell surface and signal transduction of full-length, membrane-tethered TREM2 in cultured cells, 39 but the functional implications of glycosylation at N20 and N79 for the soluble TREM2 ectodomain remain to be determined.…”

Section: ■ Results and Discussionmentioning

confidence: 99%

Total Chemical Synthesis of Glycosylated TREM2 Ectodomain

Wijegunawardena

Castillo

Henrickson

et al. 2023

ACS Chem. Neurosci.

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Mutations in a microglia-associated gene TREM2 increase the risk of Alzheimer’s disease. Currently, structural and functional studies of TREM2 mainly rely on recombinant TREM2 proteins expressed from mammalian cells. However, using this method, it is difficult to achieve site-specific labeling. Here, we present the total chemical synthesis of the 116 amino acid TREM2 ectodomain. Rigorous structural analysis ensured correct structural fold after refolding. Treating microglial cells with refolded synthetic TREM2 enhanced microglial phagocytosis, proliferation, and survival. We also prepared TREM2 constructs with defined glycosylation patterns and found that glycosylation at N79 is critical to the thermal stability of TREM2. This method will provide access to TREM2 constructs with site-specific labeling, such as fluorescent labeling, reactive chemical handles, and enrichment handles, to further advance our understanding of TREM2 in Alzheimer’s disease.

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Section: ■ Results and Discussionmentioning

confidence: 99%

Total Chemical Synthesis of Glycosylated TREM2 Ectodomain

Wijegunawardena

Castillo

Henrickson

et al. 2023

ACS Chem. Neurosci.

View full text Add to dashboard Cite

show abstract

“…Taken together, the thermal denaturation study identified a critical role of N79 glycosylation on the thermal stability of TREM2. Interestingly, these two N glycans were shown to facilitate trafficking to the cell surface and signal transduction of full-length, membrane-tethered TREM2 in cultured cells, 39 but the functional implications of glycosylation at N20 and N79 for soluble TREM2 ectodomain remains to be determined.…”

Section: Refolded Synthetic Trem2(19-134) Enhanced Microglial Phagocy...mentioning

confidence: 99%

Total Chemical Synthesis of Glycosylated TREM2 Ectodomain

Wijegunawardena

Castillo

Henrickson

et al. 2023

Preprint

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Mutations in a microglia-associated gene TREM2 increase the risk of Alzheimer's disease. Currently, structural and functional studies of TREM2 mainly rely on recombinant TREM2 proteins expressed from mammalian cells. However, using this method, it is difficult to achieve site-specific labeling. Here we present the total chemical synthesis of the 116 amino-acid TREM2 ectodomain. Rigorous structural analysis ensured correct structural fold after refolding. Treating microglial cells with refolded synthetic TREM2 enhanced microglial phagocytosis, proliferation, and survival. We also prepared TREM2 constructs with defined glycosylation patterns and found that glycosylation at N79 is critical to the thermal stability of TREM2. This method will provide access to TREM2 constructs with site-specific labeling, such as fluorescent labeling, reactive chemical handles, and enrichment handles, to further advance our understanding of TREM2 in Alzheimer's disease.

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“…24 N-linked glycosylation of Trem2-FL affects its stability, trafficking to the PM, and post-activation signal transduction. 25 However, the effects of sialylation on Trem2 remain elusive.…”

Section: Introductionmentioning

confidence: 99%

Neuraminidase 1 regulates the cellular state of microglia by modulating the sialylation of Trem2

Fremuth,

Hu,

van de Vlekkert

et al. 2024

Preprint

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Neuraminidase 1 (NEU1) cleaves terminal sialic acids from sialoglycoproteins in endolysosomes and at the plasma membrane. As such, NEU1 regulates immune cells, primarily those of the monocytic lineage. Here we examined how Neu1 influences microglia by modulating the sialylation of full-length Trem2 (Trem2-FL), a multifunctional receptor that regulates microglial survival, phagocytosis, and cytokine production. When Neu1 was deficient/downregulated, Trem2-FL remained sialylated, accumulated intracellularly, and was excessively cleaved into a C-terminal fragment (Trem2-CTF) and an extracellular soluble domain (sTrem2), enhancing their signaling capacities. Sialylated Trem2-FL (Sia-Trem2-FL) did not hinder Trem2-FL-DAP12-Syk complex assembly but impaired signal transduction through Syk, ultimately abolishing Trem2-dependent phagocytosis. Concurrently, Trem2-CTF-DAP12 complexes dampened NFkB signaling, while sTrem2 propagated Akt-dependent cell survival and NFAT1 mediated production of TNFa and CCL3. Because NEU1 and Trem2 are implicated in neurodegenerative/neuroinflammatory diseases, including Alzheimer disease (AD) and sialidosis, modulating NEU1 activity represents a therapeutic approach to broadly regulate microglia-mediated neuroinflammation.

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The role of TREM2 N-glycans in trafficking to the cell surface and signal transduction of TREM2

Cited by 6 publications

References 39 publications

Total Chemical Synthesis of Glycosylated TREM2 Ectodomain

Total Chemical Synthesis of Glycosylated TREM2 Ectodomain

Total Chemical Synthesis of Glycosylated TREM2 Ectodomain

Neuraminidase 1 regulates the cellular state of microglia by modulating the sialylation of Trem2

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