Pro-inflammatory cytokine IFN-γ protects against renal fibrosis by promoting E3 ubiquitin ligase Trim21-mediated Loxl2 degradation in tubular epithelial cells

Abstract The excessive accumulation of extracellular matrix (ECM) is a hallmark of renal interstitial fibrosis, its underlying mechanisms are incompletely understood. Here, we identify the E3 ubiquitin ligase Tripartite motif-containing protein 21 (Trim21) as a key regulator of this process. We found that Trim21 is upregulated in the tubular cells of fibrotic kidneys from both chronic kidney disease (CKD) patients and mouse models. Using tubular cell-specific Trim21 knockout mice, we demonstrated that Trim21 induction protects against ECM accumulation and renal fibrosis. Mechanistically, Trim21 binds to the N-terminal domain of Lysyl Oxidase-like 2 (Loxl2), promoting its ubiquitination and degradation, which in turn alleviates ECM deposition. Furthermore, we observed an upregulation of interferon-γ (IFN-γ) and its receptor in tubular cells during fibrosis. IFN-γ treatment increased Trim21 expression, reduced Loxl2 expression and renal fibrosis; critically, this protective effect was abolished in tubular-specific Trim21 knockout mice. In summary, our study defines a protective IFN-γ/Trim21/Loxl2 axis in the kidney, wherein IFN-γ signaling induces Trim21 to target Loxl2 for degradation, thereby mitigating fibrosis.