The TREM2-DAP12 signaling pathway in Nasu–Hakola disease: a molecular genetics perspective

Figures & data

Table 1 TREM2 and TYROBP mutations identified in PLOSL

Mutation	Location	TREM2/TYROBP function change	Country	Reference
TYROBP
Del 5.3 kb	Exons 1–4	No TYROBP expression	Finland, Norway, Sweden	12
Del 8 kb	Exons 1–4	No TYROBP expression	Brazil	13
141 DelG	Exon 3	Frame shift, truncated DAP12 protein	Japan	12,18
2 T>C	Exon I	Met1Thr, no TYROBP expression	Japan	18
145 G>C	Exon 3	Nonfunctional truncated DAP12	Portugal	20
262 G>T	Exon 4	Glu87Stp	Japan	19
154– 155ins42nt	Exon 3	Insertion of 14 aa	UK	21
TREM2
40 G→T	Exon I	Nonfunctional TREM2	Germany	26
97 C>T	Exon 2	Gln33Stp, truncated TREM2 protein	Belgium, Italy	13
132 G>A	Exon 2	Truncated TREM2 protein	Bolivia	13
267 DelG	Exon 2	Frame shift	France	21
3I3 DelG	Exon 2	Frame shift	Germany	21
377 T>G	Exon 2	Val126Gly	Canada, UK	21
401 A>G	Exon 3	Asp134Gly, truncated TREM2 protein	USA	13
482+2 T>C	Intron 3	Splicing mutation, no functional TREM2	Italy	13
558 G>A	Exon 4	TREM2 DAP12 no interaction	Norway	13

Abbreviations: TREM2, triggering receptor expressed on myeloid cells-2; PLOSL, polycystic lipomembranous osteodysplasia with sclerosing leukoencephalopathy; Del, deletion; Stp, stop codon; aa, amino acid; DAP12, DNAX-activating protein 12.

Figure 1 Multimeric or high-affinity ligand-induced TREM2 signaling promotes myeloid cell activation.

Notes: In response to high-affinity ligand binding to heavily glycosylated TREM2, Src family kinases phosphorylate the two tyrosines within ITAM of DAP12 and the YINM motif of DAP10, which forms docking sites for the Syk and PI3K. PI3K converts PIP2 to PIP3 leading to the recruitment of LAB adapter protein and multiple signaling effectors including SLP-76, PLC-γ2, AKT, VAV3, Tec kinases, and Grb2. This signaling complex then leads to the activation of ERK, CARD9, calcineurin, ROS, and calcium flux. These signals increase activation and nuclear localization of transcription factors AP1, NF-κB, and NFAT to promote cell proliferation, cell survival, phagocytosis, pro-inflammatory cytokine production, and cytoskeletal rearrangement.
Abbreviations: TREM2, triggering receptor expressed on myeloid cells-2; ITAM, immunoreceptor tyrosine-based activation motif; DAP12, DNAX-activating protein 12; Syk, spleen tyrosine kinase; PI3K, phosphatidylinositol-3 kinase; PIP2, phosphatidylinositol-4,5-bisphosphate; PIP3, phosphatidylinositol-3,4,5-trisphosphate; LAB, linker for the activation of B cells; SLP-76, Src homology 2 domain-containing leukocyte protein of 76 kDa; PLC-γ2, phospholipase C gamma-2; Grb2, growth factor-receptor-bound protein 2; ROS, reactive oxygen species; NFAT, nuclear factor activated T cell; SOS1, son of sevenless homolog1; DAG, diacylglycerol; IP3, inositol-1,4,5-trisphosphate; PKC, protein kinase C; RasGRP, Ras guanyl nucleotide-releasing protein; CaMK, calmodulin-dependent kinase.

Figure 2 Monovalent or weak ligand-induced TREM2 signaling is anti-inflammatory.

Notes: During tonic ITAM signaling such as that resulting from a weak or monovalent ligand, SHIP1 is recruited to the DAP12 ITAM where it competes with and prevents further recruitment of SH2 domain-containing proteins, including PI3K and Syk. This leads to an arrest in the activation of PI3K, PLC-γ, MAPK, and NF-κB. Tonic calcium flux resulting from ligand binding contributes to calcineurin activation that in turn inhibits TLR-associated MyD88 to limit TLR-induced pro-inflammatory cytokine production. Tonic calcium flux also induces NFAT activation promoting inhibitory cytokine production including IL-10.
Abbreviations: TREM2, triggering receptor expressed on myeloid cells-2; ITAM, immunoreceptor tyrosine-based activation motif; SHIP1, SH2 domain-containing inositol phosphatase-1; DAP12, DNAX-activating protein 12; SH2, Src homology 2; PI3K, phosphatidylinositol-3 kinase; Syk, spleen tyrosine kinase; PLC-γ2, phospholipase C gamma-2; MAPK, mitogen-activated protein kinase; TLR, Toll-like receptor; NFAT, nuclear factor activated T cell; IL-10, interleukin-10; LAB, linker for the activation of B cells; SLP-76, SH2 domain-containing leukocyte protein of 76 kDa; Grb2, growth factor-receptor-bound protein 2; DOK3, downstream of kinases 3; SOS1, son of sevenless homolog1.