Condensation of cellular prion protein promotes renal fibrosis through the TBK1-IRF3 signaling axis
Tantan Long, Yumei Lu, Yuanyuan Ma, Yandong Song, Xiaoping Yi, Xiaomei Chen, Miaomiao Zhou, Jingyi Ma, Jiayuan Chen, Zhuoliang Liu, Fengxin Zhu, Zheng Hu, Zhanmei Zhou, Chaoyang Li, Fan Fan Hou, Lirong Zhang, Yupeng Chen, Jing Nie
Abstract
Cellular prion protein (PrP C ), 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 PrP C in the development of renal disease is unexplored. Here, we showed that PrP C 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 PrP C 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 PrP C mitigated renal fibrosis induced by unilateral ureteral obstruction (UUO) or unilateral ischemia-reperfusion injury (UIRI). Mechanistically, PrP C was up-regulated by transforming growth factor–β1–suppressor of mothers against decapentaplegic 3 signaling. PrP C 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 PrP C underlying renal fibrosis and support further study of the PrP C -TBK1-IRF3 axis as a potential therapeutic target for CKD.