Pellino1-mTOR/S6K1 signaling axis is a key pathogenesis for the development of polycystic kidney disease.

Ubiquitination serves a critical role in regulating both inflammatory responses and kidney injury. Among inherited renal disorders, autosomal dominant polycystic kidney disease (ADPKD) has demonstrated associations with disrupted ubiquitin signaling that exacerbates inflammation and cyst progression. In this study, we demonstrate that the E3 ligase Pellino1 (Peli1) acts as an essential contributor to the pathogenesis of ADPKD amid inflammatory conditions. In individuals with clear cell renal cell carcinoma (ccRCC), Peli1 exhibits markedly elevated expression, and this upregulation is associated with adverse clinical outcomes. Additionally, we find that various TLR stimulations in renal tubular cells induce increased Peli1 expression, which is also elevated in samples from ADPKD patients. Using doxycycline-inducible Peli1-transgenic mice, we establish that Peli1 overexpression leads to impaired renal function and facilitates cyst formation. On a mechanistic level, elevated Peli1 promotes cystic epithelial cell proliferation by activating mTOR signaling, accomplished through the stabilization of S6K1. In summary, our data indicate that TLR-driven upregulation of Peli1 facilitates renal cyst growth via S6K1 stabilization. These results reveal a novel mechanistic link between PKD and ccRCC. A schematic model is proposed to describe the role of Peli1 in the development of polycystic kidney diseases. Normal signaling pathways (Left) and Peli1-mediated signaling pathways in polycystic kidney disease (Right). The illustration outlines the cascade from TLR stimulation to Peli1-dependent K63 ubiquitination of S6K1 and subsequent proliferation in renal tubular epithelial cells. This figure was generated using BioRender.com.