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

Lysosome impairment causes cellular and organ dysfunction, highlighting its crucial role in homeostasis. 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. Moreover, in vivo RNA-seq and cytokine profiling demonstrated enrichment of immune-related pathways and IL-11 production in Gak-KO podocytes. Overall, this study underscores the importance of lysosome integrity and suggests how its dysfunction may lead podocytes to adopt immune-like properties, with potential autocrine and paracrine effects within the kidney.