2. Academic Validation
  3. Condensation of cellular prion protein promotes renal fibrosis through the TBK1-IRF3 signaling axis

Condensation of cellular prion protein promotes renal fibrosis through the TBK1-IRF3 signaling axis

  • Sci Transl Med. 2025 Apr 16;17(794):eadj9095. doi: 10.1126/scitranslmed.adj9095.
Tantan Long 1,  Yumei Lu 2,  Yuanyuan Ma 1,  Yandong Song 2,  Xiaoping Yi 2,  Xiaomei Chen 1,  Miaomiao Zhou 1,  Jingyi Ma 1,  Jiayuan Chen 2,  Zhuoliang Liu 1,  Fengxin Zhu 1,  Zheng Hu 1,  Zhanmei Zhou 1,  Chaoyang Li 3 4 5,  Fan Fan Hou 1,  Lirong Zhang 2,  Yupeng Chen 2,  Jing Nie 1 6 7
Affiliations

Affiliations

  • 1 State Key Laboratory of Organ Failure Research, National Clinical Research Center for Kidney Disease, Guangdong Provincial Key Laboratory of Renal Failure Research, Guangdong Provincial Institute of Nephrology, Nanfang Hospital, Southern Medical University, Guangzhou 510515, China.
  • 2 Province and Ministry Co-sponsored Collaborative Innovation Center for Medical Epigenetics, Key Laboratory of Immune Microenvironment and Disease (Ministry of Education), State Key Laboratory of Experimental Hematology, Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Tianjin Medical University, Tianjin 300070, China.
  • 3 Hunan Engineering Research Center for Early Diagnosis and Treatment of Liver Cancer, Hunan Province Key Laboratory of Tumor Cellular and Molecular Pathology, Cancer Research Institute, School of Basic Medical Sciences, University of South China, Hengyang 421001, China.
  • 4 Guangzhou Municipal and Guangdong Provincial Key Laboratory of Protein Modification and Degradation, School of Basic Medical Sciences, Guangzhou Medical University, Guangzhou 511436, China.
  • 5 Guangzhou Institute of Cancer Research, Affiliated Cancer Hospital, Guangzhou Medical University, State Key Laboratory of Respiratory Disease, Guangzhou 510095, China.
  • 6 Biobank of Peking University First Hospital, Peking University First Hospital, Beijing 100034, China.
  • 7 State Key Laboratory of Vascular Homeostasis and Remodeling, Peking University Health Science Center, Beijing 100191, China.
PMID: 40238918 DOI: 10.1126/scitranslmed.adj9095
Abstract

Cellular Prion Protein (PrPC), known for its pathological isoform in prion diseases such as Creutzfeldt-Jakob disease, is primarily expressed in the nervous system but has also been detected in the blood and urine of individuals with renal dysfunction. However, the role of PrPC in the development of renal disease is unexplored. Here, we showed that PrPC was up-regulated in fibrotic renal lesions in biopsies from patients with chronic kidney disease (CKD), predominantly in proximal tubular epithelial cells (PTECs). Furthermore, renal expression of PrPC was positively correlated with the severity of renal failure and the decline in estimated glomerular filtration rate in patients with CKD. In mice, tubular-specific deletion of PrPC mitigated renal fibrosis induced by unilateral ureteral obstruction (UUO) or unilateral ischemia-reperfusion injury (UIRI). Mechanistically, PrPC was up-regulated by transforming growth factor-β1-suppressor of mothers against decapentaplegic 3 signaling. PrPC activated TANK binding kinase 1 (TBK1)-interferon regulatory factor 3 (IRF3) signaling through its capacity for liquid-liquid phase separation, which promoted a profibrotic response in PTECs and fibroblasts. Treating mice with amlexanox, a US Food and Drug Administration-approved inhibitor of TBK1, either before the onset of renal fibrosis (in UUO and UIRI models) or after its establishment (in adenine- and aristolochic acid-induced CKD models), mitigated worsening of renal fibrosis and renal function. Collectively, our findings uncovered a mechanism involving phase separation of PrPC underlying renal fibrosis and support further study of the PrPC-TBK1-IRF3 axis as a potential therapeutic target for CKD.

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