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

J Biol Chem. 2012 Aug 24;287(35):29620-6. doi: 10.1074/jbc.M112.351239. Epub 2012 Jul 3.


Triggering receptor expressed on myeloid cells (TREM)-like transcript-1 (TLT-1) is an immunoreceptor tyrosine-based inhibitory motif (ITIM)-baring TREM family protein. In this study, we identified an alternative transcript form of TLT-1, namely TLT-1s, which has very short extracellular immunoglobulin domain consisting of only 202 amino acids. TLT-1s was mainly expressed in macrophages and osteoclast precursor cells. Upon receptor activator of nuclear factor-κB ligand stimulation, TLT-1s mRNA and protein levels were gradually decreased in BMMs. We also showed the TLT-1s is localized to the cytoplasmic membrane in osteoclast precursor cells. TLT-1s silencing strongly enhanced the formation and resorption activity of osteoclast. In addition, forced expression of TLT-1s showed reduced formation of osteoclast. Because ITIM-baring proteins inhibit immunoreceptor tyrosine-based activation motif (ITAM)-mediated receptor signaling, we tested whether TLT-1s physically interacted with TREM-2, the ITAM-associated co-stimulatory receptor essential for osteoclast differentiation. We showed that TLT-1s is associated with TREM-2 in osteoclast precursor cells. TLT-1s is also associated with tyrosine Src homology 2 domain-containing phosphatase-1 and SH2 domain-containing inositol phosphatase-1 and recruited them to the TREM2-ITAM signaling complex. In addition, knockdown of TLT-1s markedly elevated the intracellular calcium concentration and oscillation in osteoclast precursor cells. In addition, calcium-mediated induction of nuclear factor of activated T cells was also increased by TLT-1s silencing. Furthermore, TREM-2-mediated Akt activation and proliferation of osteoclast precursor cells were also enhanced in TLT-1s silenced cells. In this paper, we found the noble ITIM-baring inhibitory membrane protein; TLT-1s, which regulates ITAM-mediated signaling on osteoclastogenesis.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Alternative Splicing / physiology*
  • Amino Acid Motifs
  • Animals
  • Cell Membrane / genetics
  • Cell Membrane / metabolism
  • Cells, Cultured
  • Enzyme Activation / physiology
  • Gene Silencing
  • Membrane Glycoproteins / genetics
  • Membrane Glycoproteins / metabolism*
  • Mice
  • NF-kappa B / genetics
  • NF-kappa B / metabolism
  • Osteoclasts / cytology
  • Osteoclasts / metabolism*
  • Phosphoprotein Phosphatases / genetics
  • Phosphoprotein Phosphatases / metabolism
  • Proto-Oncogene Proteins c-akt / genetics
  • Proto-Oncogene Proteins c-akt / metabolism
  • RNA, Messenger / genetics
  • RNA, Messenger / metabolism
  • Receptors, Immunologic / genetics
  • Receptors, Immunologic / metabolism*
  • Signal Transduction / physiology*
  • src Homology Domains


  • Membrane Glycoproteins
  • NF-kappa B
  • RNA, Messenger
  • Receptors, Immunologic
  • Trem2 protein, mouse
  • Treml1 protein, mouse
  • Proto-Oncogene Proteins c-akt
  • Phosphoprotein Phosphatases