The KEOPS complex catalyzes a specific post-transcriptional modification of tRNA molecules. This function is evolutionarily highly conserved but has remained poorly understood to date. It was only through our genetic investigations that a connection to human disease became apparent, leading to the hypothesis that tRNA modifications play a particularly important role in podocytes.

To gain new insights into the molecular pathomechanisms of podocyte injury based on our genetic findings, we conducted further studies using established cell culture systems. These studies yielded several interesting results:

First, we identified endoplasmic reticulum (ER) stress as a cause of podocyte injury and a trigger of apoptosis in podocytes. This finding is of particular interest because ER stress and the associated activation of the unfolded protein response (UPR) represent a promising target for novel, targeted therapies against podocyte damage.

Second, as a consequence of KEOPS loss of function, we observed a reduced rate of protein biosynthesis. Since podocytes are not secretory cells, this raises the intriguing question of why this particular cell type is especially vulnerable to disturbances in protein biosynthesis—an avenue that opens up interesting perspectives for further research.

In addition, we identified a series of secondary phenomena that underscore the central role of the KEOPS complex in podocytes, such as genomic stress with activation of the DNA damage response cascade and disturbances in actin homeostasis.

In summary, we discovered a previously unknown pathogenic mechanism of podocyte injury, characterized the resulting cellular defects, and identified a promising new target for future therapeutic interventions.

Our current work employs various cell culture systems, transcriptome analyses, and relevant animal models (particularly mouse and Drosophila melanogaster), to further elucidate the pathogenesis of KEOPS-associated podocyte diseases (DFG project number 391152220).