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Peer-reviewedCC BY-NC-ND 4.0Communications Biology

Cathepsin resistance mediated by key amino acid substitutions drives intracellular crystallization in light chain proximal tubulopathy

  • Xin Wang1,2,3,4,5,6
  • Shuang Wang1,3,4,5,6,7,8
  • Chu-qiao Wang1,3,4,5,6,7
  • Yue-yue Zhu1,3,4,5,6,7,8
  • Xin Zhang1,3,4,5,6,7
  • Jin Xu8
  • Yi Liu9
  • Xiao-juan Yu1,3,4,5,6,7
  • Su-xia Wang1,3,4,5,6,7,8
  • Li Yang1,3,4,5,6,7
  • Fu-de Zhou1,3,4,5,6,7
  • Ming-hui Zhao1,2,3,4,5,6,7
9 affiliations
  1. 1Renal Division, Department of Medicine, Peking University First Hospital, Beijing, China
  2. 2Peking-Tsinghua Center for Life Sciences, Beijing, China
  3. 3Institute of Nephrology, Peking University, Beijing, China
  4. 4Renal Pathology Center, Institute of Nephrology, Peking University, Beijing, China
  5. 5Key Laboratory of Renal Disease, Ministry of Health of China, Beijing, China
  6. 6Key Laboratory of CKD Prevention and Treatment, Ministry of Education of China, Beijing, China
  7. 7Research Unit of Diagnosis and Treatment of Immune-Mediated Kidney Diseases, Chinese Academy of Medical Sciences, Beijing, China
  8. 8Laboratory of Electron Microscopy, Pathological Center, Peking University First Hospital, Beijing, China
  9. 9Key Laboratory of Combinatorial Biosynthesis and Drug Discovery, Ministry of Education, School of Pharmaceutical Sciences, Wuhan University, Wuhan, China
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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.

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Cite

BibTeXRIS
BibTeX
@article{wang2026cathepsin,
  title = {{Cathepsin resistance mediated by key amino acid substitutions drives intracellular crystallization in light chain proximal tubulopathy}},
  author = {Xin Wang and Shuang Wang and Chu-qiao Wang and Yue-yue Zhu and Xin Zhang and Jin Xu and Yi Liu and Xiao-juan Yu and Su-xia Wang and Li Yang and Fu-de Zhou and Ming-hui Zhao},
  journal = {Communications Biology},
  year = {2026},
  month = jul,
  doi = {10.1038/s42003-026-10589-y},
  url = {https://doi.org/10.1038/s42003-026-10589-y},
  note = {CC BY-NC-ND 4.0},
}
RIS
TY  - JOUR
TI  - Cathepsin resistance mediated by key amino acid substitutions drives intracellular crystallization in light chain proximal tubulopathy
AU  - Xin Wang
AU  - Shuang Wang
AU  - Chu-qiao Wang
AU  - Yue-yue Zhu
AU  - Xin Zhang
AU  - Jin Xu
AU  - Yi Liu
AU  - Xiao-juan Yu
AU  - Su-xia Wang
AU  - Li Yang
AU  - Fu-de Zhou
AU  - Ming-hui Zhao
PY  - 2026
DA  - 2026/07/07
JO  - Communications Biology
DO  - 10.1038/s42003-026-10589-y
UR  - https://doi.org/10.1038/s42003-026-10589-y
AB  - 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.
SN  - 2399-3642
ER  -