DEPDC5, or Dishevelled, Egl-10 and Pleckstrin domain-containing protein 5, is a protein subunit of the GTPase-activating proteins towards Rags 1 (GATOR1) complex. GATOR1 modulates the mechanistic target of rapamycin (mTOR) activity, and mTOR is a key regulator of cell proliferation and metabolism. Thus, DEPDC5 is important in regulating the mTOR pathway, which is involved in many biological processes and is disrupted in various diseases, especially epilepsy [2]. Genetic models, like knockout (KO) mouse models, have been crucial in studying its function.

In mice with T cell-specific Depdc5 deletion, there is a reduction in peripheral CD8+ T cells and impaired anti-tumor immunity. Mechanistically, Depdc5-deficient CD8+ T cells have high levels of xanthine oxidase and lipid ROS due to hyper-mTORC1-induced expression of ATF4, leading to spontaneous ferroptosis [1]. In Depdc5 hepatocyte-specific knockout mouse model (Depdc5-LKO), the constitutive activation of mTORC1 pathway through loss of GATOR1's inhibitory effect exacerbates alcohol-induced hepatic steatosis, which can be reversed by suppressing mTORC1 activity or activating peroxisome proliferator activated receptor α (PPARα) [3]. In Depdc5 neuronal-specific knockout mice, they are resistant to sensing brain amino acid level fluctuations after fasting and the protective effects of fasting on seizures or seizure-induced death, indicating acute fasting reduces seizure susceptibility in a DEPDC5-dependent manner [4].

In conclusion, Depdc5 plays a vital role in multiple biological processes mainly through its regulation of the mTOR pathway. Mouse KO models have revealed its functions in T cell homeostasis, anti-tumor immunity, alcohol-related liver disease, and epilepsy. These findings contribute to understanding the underlying mechanisms of related diseases and potentially developing new therapeutic strategies.