Abstract
The surface receptor triggering receptor expressed on myeloid cells 2 (TREM2) plays a crucial role in maintaining a multitude of microglial activities, such as survival, proliferation, migration, metabolism, inflammation, and phagocytosis. However, the molecular mechanisms underlying TREM2-mediated microglial activities remain largely elusive. Herein, we found that TREM2 interacted with the type I transmembrane protein TMEM59, whose expression could facilitate autophagic flux through its carboxyl-terminus. TMEM59 expression was decreased upon lipopolysaccharide treatment. While downregulation of TMEM59 promoted anti-inflammatory factor expression and attenuated lipopolysaccharide treatment-induced inflammation. Importantly, we found that overexpression of TREM2 reduced TMEM59 protein levels through promoting its degradation, whereas TMEM59 levels were elevated in Trem2-deficient microglia. Finally, impaired survival, proliferation, migration, and phagocytosis, as well as dysregulated autophagy and metabolism in Trem2-deficient microglia were attenuated upon TMEM59 silencing. Together, our findings reveal a novel function of TREM2 in mediating TMEM59 protein degradation and demonstrate the importance of TMEM59 homeostasis in maintaining TREM2-mediated microglial activities.
Highlights
Microglia are the principal immune cells residing in the central nervous system (CNS) and crucial for brain immunosurveillance[1]
When different TMEM59 plasmids were co-transfected with a GFP-tagged LC3B plasmid into BV2 cells, we found that both full length TMEM59 (Fig. 1c) and TMEM59-carboxylterminal fragment (CTF) (Fig. 1d) interacted with LC3B, whereas TMEM59-NTF did not (Fig. 1e)
Our results suggest that TMEM59 promotes autophagy through its CTF
Summary
Microglia are the principal immune cells residing in the central nervous system (CNS) and crucial for brain immunosurveillance[1]. Alzheimer’s disease (AD) is the most common neurodegenerative disease and multiple genes important for maintaining normal microglia functions, such as triggering receptor expressed on myeloid cells 2 (TREM2), apolipoprotein E (APOE), complement receptor 1 (CR1), cluster of differentiation 33 (CD33), and ATP-binding. In the CNS, TREM2 is dominantly expressed in microglia and interacts with the protein adaptor DAP12, which transmits intracellular signals upon ligand binding of TREM28. It has been reported that the extracellular domain of TREM2 can bind to bacterial lipopolysaccharide (LPS)[9], phospholipids[10], amyloid-β (Aβ) oligomers[11,12,13], APOE and APOJ and related lipoproteins[14,15,16], and apoptotic neurons[17]. Homozygous loss-of-function mutations in TREM2 as well as DAP12 have been reported to cause Nasu–Hakola disease (NHD), in which patients develop systemic bone cysts and presenile dementia[22,23]. Heterozygous TREM2 mutations have been found to be associated with AD24–26, and with Parkinson’s
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