2. Academic Validation
  3. DAP12 Stabilizes the C-terminal Fragment of the Triggering Receptor Expressed on Myeloid Cells-2 (TREM2) and Protects against LPS-induced Pro-inflammatory Response

DAP12 Stabilizes the C-terminal Fragment of the Triggering Receptor Expressed on Myeloid Cells-2 (TREM2) and Protects against LPS-induced Pro-inflammatory Response

  • J Biol Chem. 2015 Jun 19;290(25):15866-15877. doi: 10.1074/jbc.M115.645986.
Li Zhong 1,  Xiao-Fen Chen 2,  Zhen-Lian Zhang 1,  Zhe Wang 1,  Xin-Zhen Shi 1,  Kai Xu 1,  Yun-Wu Zhang 1,  Huaxi Xu 3,  Guojun Bu 4
Affiliations

Affiliations

  • 1 Fujian Provincial Key Laboratory of Neurodegenerative Disease and Aging Research, Institute of Neuroscience, Medical College, Xiamen University, Xiamen 361102, PR China.
  • 2 Fujian Provincial Key Laboratory of Neurodegenerative Disease and Aging Research, Institute of Neuroscience, Medical College, Xiamen University, Xiamen 361102, PR China. Electronic address: chenxf@xmu.edu.cn.
  • 3 Fujian Provincial Key Laboratory of Neurodegenerative Disease and Aging Research, Institute of Neuroscience, Medical College, Xiamen University, Xiamen 361102, PR China; Degenerative Disease Research Program, Center for Neuroscience, Aging, and Stem Cell Research, Sanford-Burnham Medical Research Institute, La Jolla, California 92037.
  • 4 Fujian Provincial Key Laboratory of Neurodegenerative Disease and Aging Research, Institute of Neuroscience, Medical College, Xiamen University, Xiamen 361102, PR China; Department of Neuroscience, Mayo Clinic, Jacksonville, Florida 32224. Electronic address: bu.guojun@mayo.edu.
PMID: 25957402 DOI: 10.1074/jbc.M115.645986
Abstract

Triggering receptor expressed on myeloid cells 2 (TREM2) is a DAP12-associated receptor expressed in microglia, macrophages, and Other myeloid-derived cells. Previous studies have suggested that TREM2/DAP12 signaling pathway reduces inflammatory responses and promotes phagocytosis of apoptotic neurons. Recently, TREM2 has been identified as a risk gene for Alzheimer disease (AD). Here, we show that DAP12 stabilizes the C-terminal fragment of TREM2 (TREM2-CTF), a substrate for γ-secretase. Co-expression of DAP12 with TREM2 selectively increased the level of TREM2-CTF with little effects on that of full-length TREM2. The interaction between DAP12 and TREM2 is essential for TREM2-CTF stabilization as a mutant form of DAP12 with disrupted interaction with TREM2 failed to exhibit such an effect. Silencing of either Trem2 or Dap12 gene significantly exacerbated pro-inflammatory responses induced by lipopolysaccharides (LPS). Importantly, overexpression of either full-length TREM2 or TREM2-CTF reduced LPS-induced inflammatory responses. Taken together, our results support a role of DAP12 in stabilizing TREM2-CTF, thereby protecting against excessive pro-inflammatory responses.

Keywords

Alzheimer disease; DAP12; TREM-CTF; TREM2; cytokine; inflammation; lipopolysaccharide (LPS); microglia; γ-secretase.

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