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

ABSTRACT: 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.

ORGANISM(S): Mus musculus

PROVIDER: GSE302106 | GEO | 2026/06/18

REPOSITORIES: GEO

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