Loss of Cyclin G–Associated Kinase Leads to Lysosome Dysfunction and Immune Modulation in Podocytes
Abstract
KEY POINTS: Loss of podocyte-associated cyclin G-associated kinase resulted in mistrafficking of lysosomal hydrolases. Loss of podocyte-associated cyclin G-associated kinase induced immune modulation. BACKGROUND: Given the postmitotic nature of podocytes, adapting to both physiologic and pathologic stress is crucial to prevent podocyte loss. An important component of maintaining cellular homeostasis are lysosomes, which are membrane-bound organelles responsible for degradation and recycling of damaged organelles and other macromolecules. Lysosome impairment has been shown to cause cellular and organ dysfunction, highlighting its crucial role in homeostasis. METHODS: We previously showed that podocyte-specific loss of cyclin G-associated kinase knockout ( Gak -KO) leads to severe proteinuria, podocyte injury, and kidney failure. To interrogate which GAK domains are necessary for its function, we used a transgenic mouse expressing a truncated 62-kDa C -terminal GAK protein (GAK C62), which consists of the clathrin-binding and J domains. We evaluated the functional role of GAK C62 in podocytes using immunofluorescence, western blotting, and in vivo transcriptomic analysis. RESULTS: Our findings revealed significant accumulation of autophagic vesicles in Gak -KO podocytes. By systematically probing for potential causes of autophagosome accumulation, we showed that loss of Gak resulted in impaired lysosomal degradation, secondary to mistrafficking of lysosomal hydrolases. Notably, GAK C62 expression completely rescued these phenotypes at the cellular and organismal levels. Moreover, in vivo translating ribosome affinity purification sequencing and cytokine profiling demonstrated enrichment of immune-related pathways and IL-11 production in Gak -KO podocytes. CONCLUSIONS: GAK, specifically its C -terminal domains, plays an important role in podocyte lysosome homeostasis. Lysosomal dysfunction due to loss of Gak led podocytes to adopt immune-like properties characterized by the release of proinflammatory cytokine IL-11.
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BibTeX
@article{bunda2026loss,
title = {{Loss of Cyclin G–Associated Kinase Leads to Lysosome Dysfunction and Immune Modulation in Podocytes}},
author = {Patricia Bunda and Xuefei Tian and Soichiro Nagata and Gabriel Lerner and Paulina Medina-Rangel and Jianlei Gu and Hongyu Zhao and Lois Greene and Shawn Ferguson and Kazunori Inoue and Shuta Ishibe},
journal = {Journal of the American Society of Nephrology},
year = {2026},
month = may,
doi = {10.1681/asn.0000001130},
url = {https://hal.science/hal-05785863v1},
note = {CC BY},
}
RIS
TY - JOUR
TI - Loss of Cyclin G–Associated Kinase Leads to Lysosome Dysfunction and Immune Modulation in Podocytes
AU - Patricia Bunda
AU - Xuefei Tian
AU - Soichiro Nagata
AU - Gabriel Lerner
AU - Paulina Medina-Rangel
AU - Jianlei Gu
AU - Hongyu Zhao
AU - Lois Greene
AU - Shawn Ferguson
AU - Kazunori Inoue
AU - Shuta Ishibe
PY - 2026
DA - 2026/05/18
JO - Journal of the American Society of Nephrology
DO - 10.1681/asn.0000001130
UR - https://hal.science/hal-05785863v1
AB - KEY POINTS: Loss of podocyte-associated cyclin G-associated kinase resulted in mistrafficking of lysosomal hydrolases. Loss of podocyte-associated cyclin G-associated kinase induced immune modulation. BACKGROUND: Given the postmitotic nature of podocytes, adapting to both physiologic and pathologic stress is crucial to prevent podocyte loss. An important component of maintaining cellular homeostasis are lysosomes, which are membrane-bound organelles responsible for degradation and recycling of damaged organelles and other macromolecules. Lysosome impairment has been shown to cause cellular and organ dysfunction, highlighting its crucial role in homeostasis. METHODS: We previously showed that podocyte-specific loss of cyclin G-associated kinase knockout ( Gak -KO) leads to severe proteinuria, podocyte injury, and kidney failure. To interrogate which GAK domains are necessary for its function, we used a transgenic mouse expressing a truncated 62-kDa C -terminal GAK protein (GAK C62), which consists of the clathrin-binding and J domains. We evaluated the functional role of GAK C62 in podocytes using immunofluorescence, western blotting, and in vivo transcriptomic analysis. RESULTS: Our findings revealed significant accumulation of autophagic vesicles in Gak -KO podocytes. By systematically probing for potential causes of autophagosome accumulation, we showed that loss of Gak resulted in impaired lysosomal degradation, secondary to mistrafficking of lysosomal hydrolases. Notably, GAK C62 expression completely rescued these phenotypes at the cellular and organismal levels. Moreover, in vivo translating ribosome affinity purification sequencing and cytokine profiling demonstrated enrichment of immune-related pathways and IL-11 production in Gak -KO podocytes. CONCLUSIONS: GAK, specifically its C -terminal domains, plays an important role in podocyte lysosome homeostasis. Lysosomal dysfunction due to loss of Gak led podocytes to adopt immune-like properties characterized by the release of proinflammatory cytokine IL-11.
SN - 1046-6673
SN - 1533-3450
ER -