TMEM59 interacts with TREM2 and modulates TREM2-dependent microglial activities

Area of Science:

• Neuroimmunology
• Cell Biology
• Molecular Mechanisms

Background:

• Triggering receptor expressed on myeloid cells 2 (TREM2) is vital for microglial functions including survival, proliferation, migration, metabolism, inflammation, and phagocytosis.
• The precise molecular mechanisms governing TREM2-mediated microglial activities are not fully understood.

Purpose of the Study:

• To elucidate the molecular mechanisms underlying TREM2-mediated microglial functions.
• To investigate the interaction between TREM2 and the transmembrane protein TMEM59.
• To determine the role of TMEM59 in TREM2-dependent microglial homeostasis.

Main Methods:

• Investigated the interaction between TREM2 and TMEM59 using molecular biology techniques.
• Assessed the impact of lipopolysaccharide (LPS) on TMEM59 expression.
• Analyzed the effect of TREM2 overexpression and deficiency on TMEM59 protein levels.
• Examined the functional consequences of TMEM59 modulation in Trem2-deficient microglia.

Main Results:

• TREM2 interacts with TMEM59, which facilitates autophagic flux.
• LPS treatment decreased TMEM59 expression, leading to reduced inflammation.
• TREM2 overexpression promoted TMEM59 degradation, while Trem2 deficiency increased TMEM59 levels.
• Silencing TMEM59 ameliorated impaired microglial functions in Trem2-deficient cells.

Conclusions:

• TREM2 mediates TMEM59 protein degradation, revealing a novel regulatory pathway.
• TMEM59 homeostasis is essential for maintaining TREM2-dependent microglial survival, proliferation, migration, phagocytosis, autophagy, and metabolism.
• This study highlights a new mechanism controlling microglial function via the TREM2-TMEM59 axis.