CRM1-Dependent Cytoplasmic Accumulation of TRIM27 Is Associated with Glomerular Endothelial Cell Injury in Lupus Nephritis.

Protein function is closely tied to subcellular localization. Tripartite motif-containing 27 (TRIM27), a member of the tripartite motif family, has been implicated in lupus nephritis (LN), yet the mechanistic basis of its pathogenic role remains incompletely understood. We previously observed that TRIM27 overexpression affects glomerular endothelial cell (GEC) injury and that TRIM27 redistributes from the nucleus to the cytoplasm in LN-affected GECs. Here, using human renal glomerular endothelial cells (HRGECs) and MRL/lpr mice, we show that cytoplasmic TRIM27 may contribute to GEC damage. Mechanistically, TRIM27 appears to translocate to the cytoplasm through association with chromosome region maintenance 1 (CRM1), and this interaction may be promoted by putative phosphorylation at Ser493. Suppression of this phosphorylation reduces the TRIM27-CRM1 association and alleviates GEC injury. Furthermore, we found that protein kinase B (AKT) may act upstream of this process and that cytoplasmic TRIM27 may contribute to forkhead box protein O1 (FOXO1) ubiquitination and degradation, which may, in turn, lead to endothelial injury. Collectively, our findings suggest a pathway in which PI3K-dependent phosphorylation of TRIM27 is coupled to CRM1-mediated cytoplasmic accumulation, with AKT likely contributing to this process, and this cascade may lead to FOXO1 degradation and GEC damage in LN. This study provides new insights into the subcellular regulation of TRIM27 and identifies potential intervention points for mitigating glomerular injury.