Loss of Gak leads to lysosome dysfunction and immune modulation in podocytes

In this study, we uncovered the indispensable role of cyclin G-associated kinase (GAK) in maintaining podocyte lysosome integrity. We previously showed that podocyte-specific loss of Gak (Gak-KO) leads to severe proteinuria, podocyte injury, and kidney failure.

To identify which GAK domains are necessary for its function, we used a transgenic mouse expressing a truncated 62-kDa C-terminal GAK protein (GAK C62). Our findings showed significant accumulation of autophagic vesicles in Gak-KO podocytes, attributed to impaired lysosomal degradation secondary to lysosomal hydrolase mistrafficking. Notably, GAK C62 expression completely rescued these phenotypes at both cellular and organismal levels.