TLT-1s, Alternative Transcripts of Triggering Receptor Expressed on Myeloid Cell-like Transcript-1 (TLT-1), Inhibits the Triggering Receptor Expressed on Myeloid Cell-2 (TREM-2)-mediated Signaling Pathway during Osteoclastogenesis

Yoon, Soo‐Hyun; Lee, Yong Deok; Ha, Jung Min; Lee, Youngkyun; Kim, Hong-Hee

doi:10.1074/jbc.m112.351239

Cited by 20 publications

(20 citation statements)

References 22 publications

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“…A short alternatively-spliced transcript lacking much of the ectodomain (TREML1s) is also expressed in osteoclast precursors and macrophages. TREML1s co-IPs with TREM2, SHP-1, and SHIP-1 and decreases ERK, Akt, and calcium signals following RANKL stimulation [96]. Therefore, TREML1 (or TREML1s) may inhibit TREM2 signaling (Fig.…”

Section: Trem2 Signalingmentioning

confidence: 99%

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TREM2-Ligand Interactions in Health and Disease

Kober

Brett

2017

Journal of Molecular Biology

174

166

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The protein Triggering receptor expressed on myeloid cells-2 (TREM2) is an immunomodulatory receptor with a central role in myeloid cell activation and survival. In recent years, the importance of TREM2 has been highlighted by the identification of coding variants that increase risk for Alzheimer’s disease and other neurodegenerative diseases. Animal studies have further shown the importance of TREM2 in neurodegenerative and other inflammatory disease models including chronic obstructive pulmonary disease, multiple sclerosis, and stroke. A mechanistic understanding of TREM2 function remains elusive, however, due in part to the absence of conclusive information regarding the identity of endogenous TREM2 ligands. While many TREM2 ligands have been proposed, their physiological role and mechanism of engagement remain to be determined. In this review, we highlight the suggested roles of TREM2 in these diseases, recent advances in our understanding of TREM2, and discuss putative TREM2-ligand interactions and their potential roles in signaling during health and disease. We develop a model based on the TREM2 structure to explain how different TREM2 ligands might interact with the receptor and how disease-risk variants may alter ligand interactions. Finally, we propose future experimental directions to establish the role and importance of these different interactions on TREM2 function.

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Section: Trem2 Signalingmentioning

confidence: 99%

“…In addition to Plexin-A1, TREML1s co-IPs with TREM2. The structural basis for these interactions are not known, and they may be indirect through association with signaling complexes [96]. …”

Section: Trem2 Ligandsmentioning

confidence: 99%

TREM2-Ligand Interactions in Health and Disease

Kober

Brett

2017

Journal of Molecular Biology

174

166

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“…In the case of TLT-1, its ITIM-mediated signaling simply cannot regulate TREM/DAP12 units because they do not share the same expression pattern. Expression of an alternate transcript of TLT-1 called TLT-1s has been found on bone marrow-derived macrophages (89). TLT-1s was shown to interact with TREM-2 via immunoprecipitation, and exogenous over-expression of TLT-1s inhibited osteoclast differentiation of bone marrow-derived macrophages.…”

Section: Tlt Receptor Functions and Therapeutic Applicationsmentioning

confidence: 99%

“…TLT-1s was shown to interact with TREM-2 via immunoprecipitation, and exogenous over-expression of TLT-1s inhibited osteoclast differentiation of bone marrow-derived macrophages. Therefore, TLT-1s ITIM-mediated signaling could be a negative regulator of TREM-2 function (89). …”

Section: Tlt Receptor Functions and Therapeutic Applicationsmentioning

confidence: 99%

Triggering receptor expressed on myeloid cells receptor family modulators: a patent review

Pelham

Pandya

Agrawal

2014

Expert Opinion on Therapeutic Patents

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Introduction Triggering receptor expressed on myeloid cells (TREM) receptors and TREM-like transcript (TLT; or TREML) receptors of the immunoglobulin superfamily are known as key modulators of host immune responses. TREM-1 (CD354) and TREM-2 share the transmembrane adaptor DNAX-activation protein of 12 kDa (DAP12), but they possess separate stimulatory and inhibitory functional roles, especially in myeloid cells. Areas covered This review covers findings related to TREMs and TLTs published in patent applications from their discovery in 2000 to the present. New roles for TREM-1, TREM-2, TLT-1 and TLT-2 in maladies ranging from acute and chronic inflammatory disorders to cardiovascular diseases and cancers are discussed. Putative endogenous ligands and novel synthetic peptide blockers are also discussed. Expert opinion So far, therapeutic use of activators/blockers specific for TREMs and TLTs has been limited to pre-clinical animal models. TREM-1 is an immediate therapeutic target for acute and chronic inflammatory conditions, especially sepsis. Certain mutations in DAP12 and TREM-2 manifest into a disorder named polycystic lipomembranous osteodysplasia with sclerosing leukoencephalopathy (PLOSL), and newly identified TREM-2 variants confer a significant increase in risk of developing Alzheimer’s disease. This makes TREM-2 an attractive therapeutic target for neurodegenerative diseases.

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“…However, TREM2-expressing macrophages can also promote inflammatory disease in the brain (Jay et al, 2015) and lung (Wu et al, 2015). The identity of a physiologic TREM2 ligand (TREM2-L) remains uncertain, although several classes of molecules have been proposed, including bacterial carbohydrates (Daws et al, 2003; Quan et al, 2008), sulfoglycolipids (Phongsisay et al, 2015), nucleic acids (Kawabori et al, 2015), phospholipids (Cannon et al, 2012; Wang et al, 2015) and proteins (Stefano et al, 2009; Takegahara et al, 2006; Yoon et al, 2012; Atagi et al, 2015; Bailey et al, 2015). Additionally, previous studies have identified cells that express a TREM2-L, including astrocytes (Daws et al, 2003), DCs (Ito and Hamerman, 2012), BMDMs (Hamerman et al, 2006), neurons and apoptotic cells (Hsieh et al, 2009).…”

Section: Introductionmentioning

confidence: 99%

Neurodegenerative disease mutations in TREM2 reveal a functional surface and distinct loss-of-function mechanisms

Kober

Alexander‐Brett

Karch

et al. 2016

eLife

169

213

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Genetic variations in the myeloid immune receptor TREM2 are linked to several neurodegenerative diseases. To determine how TREM2 variants contribute to these diseases, we performed structural and functional studies of wild-type and variant proteins. Our 3.1 Å TREM2 crystal structure revealed that mutations found in Nasu-Hakola disease are buried whereas Alzheimer’s disease risk variants are found on the surface, suggesting that these mutations have distinct effects on TREM2 function. Biophysical and cellular methods indicate that Nasu-Hakola mutations impact protein stability and decrease folded TREM2 surface expression, whereas Alzheimer’s risk variants impact binding to a TREM2 ligand. Additionally, the Alzheimer’s risk variants appear to epitope map a functional surface on TREM2 that is unique within the larger TREM family. These findings provide a guide to structural and functional differences among genetic variants of TREM2, indicating that therapies targeting the TREM2 pathway should be tailored to these genetic and functional differences with patient-specific medicine approaches for neurodegenerative disorders.DOI: http://dx.doi.org/10.7554/eLife.20391.001

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TLT-1s, Alternative Transcripts of Triggering Receptor Expressed on Myeloid Cell-like Transcript-1 (TLT-1), Inhibits the Triggering Receptor Expressed on Myeloid Cell-2 (TREM-2)-mediated Signaling Pathway during Osteoclastogenesis

Cited by 20 publications

References 22 publications

TREM2-Ligand Interactions in Health and Disease

TREM2-Ligand Interactions in Health and Disease

Triggering receptor expressed on myeloid cells receptor family modulators: a patent review

Neurodegenerative disease mutations in TREM2 reveal a functional surface and distinct loss-of-function mechanisms

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