Vps35 ‐dependent recycling of Trem2 regulates microglial function

In this study, we showed that Trem2 in the plasma membrane underwent endocytosis and recycling. Trem2 is internalized in a clathrin‐dependent manner and then recycled back to the plasma membrane through Vps35, the key component of cargo recognition core of retromer complex, but not Rab11. When Vps35 is knocked down, Trem2 accumulated in the lysosomes but not degraded. More importantly, Vps35 deficiency leads to excessive LPS‐induced iNOS expression and IL‐6 production, which can be abolished by Trem2 overexpression. Furthermore, R47H Trem2, an Alzheimer's disease‐associated mutant, failed to interact with Vps35 and became unstable compared with wild type Trem2. Our study suggests that Vps35/retromer is responsible for recycling of Trem2 in the regulation of microglial function such as pro‐inflammatory responses, whereas R47H mutation impairs Trem2 trafficking, which might contribute to Alzheimer's disease.

Model for Vps35‐mediated Trem2 recycling. Wild type Trem2 is internalized in a clathrin‐dependent manner then trafficked to cell membrane through Vps35. By recycling Trem2, Vps35 is involved in suppressing pro‐inflammatory responses of microglia. However, the R47H mutant Trem2 is impaired in interacting with Vps35 and accumulated in lysosome for degradation.

Source: Traffic - September 25, 2016 Category: Research Authors: Jie Yin, Xiaocui Liu, Qing He, Lujun Zhou, Zengqiang Yuan, Siqi Zhao Tags: Original Article Source Type: research