{
  "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.",
  "abstract_shown": true,
  "affiliations": [],
  "article_type": null,
  "arxiv": null,
  "author_total": 11,
  "authors": [
    {
      "name": "Patricia Bunda"
    },
    {
      "name": "Xuefei Tian"
    },
    {
      "name": "Soichiro Nagata"
    },
    {
      "name": "Gabriel Lerner"
    },
    {
      "name": "Paulina Medina-Rangel"
    },
    {
      "name": "Jianlei Gu"
    },
    {
      "name": "Hongyu Zhao"
    },
    {
      "name": "Lois Greene"
    },
    {
      "name": "Shawn Ferguson"
    },
    {
      "name": "Kazunori Inoue"
    },
    {
      "name": "Shuta Ishibe"
    }
  ],
  "bibtex": "https://research.draconitic.com/paper/7bnzysdjvymjh.bib",
  "cited_by": 0,
  "doi": "10.1681/asn.0000001130",
  "fulltext_url": null,
  "id": "7bnzysdjvymjh",
  "issns": [
    "1046-6673",
    "1533-3450"
  ],
  "landing_url": "https://hal.science/hal-05785863v1",
  "language": "en",
  "licence": "CC-BY",
  "licence_label": "CC BY",
  "licence_source": "journal",
  "licence_url": "https://creativecommons.org/licenses/by/4.0/",
  "metadata_licence": null,
  "native_subjects": [
    [
      "hal",
      "0.sdv"
    ],
    [
      "openalex",
      "2727|Renal Diseases and Glomerulopathies"
    ]
  ],
  "openalex": "W7161606448",
  "pdf_url": null,
  "pmcid": null,
  "pmid": null,
  "published": "2026-05-18",
  "publisher": "American Society of Nephrology",
  "ris": "https://research.draconitic.com/paper/7bnzysdjvymjh.ris",
  "sources": [
    {
      "first_seen": "2026-10-30T12:17:50Z",
      "native_id": "hal-05785863",
      "source": "hal",
      "url": "https://hal.science/hal-05785863v1"
    }
  ],
  "subjects": [
    {
      "field": "biology",
      "origin": "hal:0.sdv",
      "subfield": "general"
    }
  ],
  "title": "Loss of Cyclin G–Associated Kinase Leads to Lysosome Dysfunction and Immune Modulation in Podocytes",
  "title_text": "Loss of Cyclin G–Associated Kinase Leads to Lysosome Dysfunction and Immune Modulation in Podocytes",
  "type": "peer-reviewed",
  "updated_at": "2026-10-30T12:17:50Z",
  "url": "https://research.draconitic.com/paper/7bnzysdjvymjh",
  "venue": "Journal of the American Society of Nephrology",
  "versions": []
}