{
  "abstract": "Monoclonal free light chains drive diverse renal pathologies in plasma cell dyscrasias. However, the mechanism of light chain proximal tubulopathy remains poorly understood because sequence data are scarce. Here we characterize full-length kappa free light chains from five patients with light chain proximal tubulopathy, four of whom had intracellular crystals. All showed the highest homology to the IGKV1-33 germline, while crystal-forming light chains contained distinct single-residue substitutions. These light chains generated a stable ~12-kDa fragment resistant to digestion by cathepsin B and D, a pattern not observed in non-crystal-forming light chains. Mechanistically, a single-residue substitution contributed substantially to cathepsin D resistance and stable fragment formation. In vivo comparison of recombinant κWJJ and its single-amino acid mutant further supported an important role for this substitution in intracellular crystal formation. These findings establish a sequence-based link between impaired lysosomal processing and crystal accumulation in light chain proximal tubulopathy.",
  "abstract_shown": true,
  "affiliations": [
    "Renal Division, Department of Medicine, Peking University First Hospital, Beijing, China",
    "Peking-Tsinghua Center for Life Sciences, Beijing, China",
    "Institute of Nephrology, Peking University, Beijing, China",
    "Renal Pathology Center, Institute of Nephrology, Peking University, Beijing, China",
    "Key Laboratory of Renal Disease, Ministry of Health of China, Beijing, China",
    "Key Laboratory of CKD Prevention and Treatment, Ministry of Education of China, Beijing, China",
    "Research Unit of Diagnosis and Treatment of Immune-Mediated Kidney Diseases, Chinese Academy of Medical Sciences, Beijing, China",
    "Laboratory of Electron Microscopy, Pathological Center, Peking University First Hospital, Beijing, China",
    "Key Laboratory of Combinatorial Biosynthesis and Drug Discovery, Ministry of Education, School of Pharmaceutical Sciences, Wuhan University, Wuhan, China"
  ],
  "article_type": "research article",
  "arxiv": null,
  "author_total": 12,
  "authors": [
    {
      "affs": [
        0,
        1,
        2,
        3,
        4,
        5
      ],
      "name": "Xin Wang",
      "orcid": "0009-0006-7768-0632"
    },
    {
      "affs": [
        0,
        2,
        3,
        4,
        5,
        6,
        7
      ],
      "name": "Shuang Wang"
    },
    {
      "affs": [
        0,
        2,
        3,
        4,
        5,
        6
      ],
      "name": "Chu-qiao Wang"
    },
    {
      "affs": [
        0,
        2,
        3,
        4,
        5,
        6,
        7
      ],
      "name": "Yue-yue Zhu"
    },
    {
      "affs": [
        0,
        2,
        3,
        4,
        5,
        6
      ],
      "name": "Xin Zhang"
    },
    {
      "affs": [
        7
      ],
      "name": "Jin Xu"
    },
    {
      "affs": [
        8
      ],
      "name": "Yi Liu",
      "orcid": "0009-0003-0974-0275"
    },
    {
      "affs": [
        0,
        2,
        3,
        4,
        5,
        6
      ],
      "name": "Xiao-juan Yu",
      "orcid": "0000-0002-6017-7188"
    },
    {
      "affs": [
        0,
        2,
        3,
        4,
        5,
        6,
        7
      ],
      "name": "Su-xia Wang"
    },
    {
      "affs": [
        0,
        2,
        3,
        4,
        5,
        6
      ],
      "name": "Li Yang"
    },
    {
      "affs": [
        0,
        2,
        3,
        4,
        5,
        6
      ],
      "name": "Fu-de Zhou"
    },
    {
      "affs": [
        0,
        1,
        2,
        3,
        4,
        5,
        6
      ],
      "name": "Ming-hui Zhao",
      "orcid": "0000-0003-3340-3108"
    }
  ],
  "bibtex": "https://research.draconitic.com/paper/04gpeb544gpmr.bib",
  "cited_by": 1,
  "doi": "10.1038/s42003-026-10589-y",
  "fulltext_url": "https://pmc.ncbi.nlm.nih.gov/articles/PMC13720156/",
  "id": "04gpeb544gpmr",
  "issns": [
    "2399-3642"
  ],
  "landing_url": "https://doi.org/10.1038/s42003-026-10589-y",
  "language": "en",
  "licence": "CC-BY-NC-ND-4.0",
  "licence_label": "CC BY-NC-ND 4.0",
  "licence_source": "article",
  "licence_url": "https://creativecommons.org/licenses/by-nc-nd/4.0/",
  "metadata_licence": null,
  "native_subjects": [
    [
      "heading",
      "Article"
    ],
    [
      "openalex",
      "2720|Multiple Myeloma Research and Treatments"
    ]
  ],
  "openalex": "W7167644584",
  "pdf_url": null,
  "pmcid": "PMC13720156",
  "pmid": "42414595",
  "published": "2026-07-07",
  "publisher": "Nature Publishing Group",
  "ris": "https://research.draconitic.com/paper/04gpeb544gpmr.ris",
  "sources": [
    {
      "first_seen": "2026-11-02T12:23:59Z",
      "native_id": "PMC13720156",
      "source": "pmc",
      "url": "https://doi.org/10.1038/s42003-026-10589-y"
    }
  ],
  "subjects": [
    {
      "field": "medicine",
      "origin": "openalex:2720|Multiple Myeloma Research and Treatments",
      "subfield": "general"
    }
  ],
  "title": "Cathepsin resistance mediated by key amino acid substitutions drives intracellular crystallization in light chain proximal tubulopathy",
  "title_text": "Cathepsin resistance mediated by key amino acid substitutions drives intracellular crystallization in light chain proximal tubulopathy",
  "type": "peer-reviewed",
  "updated_at": "2026-11-03T12:21:05Z",
  "url": "https://research.draconitic.com/paper/04gpeb544gpmr",
  "venue": "Communications Biology",
  "versions": []
}