FBXO22 Suppresses Oxidative Stress-Induced ASK1 Activation and Cell Death via Ubiquitination-Dependent Degradation of TRIM48

TRIM48 is a human-specific tripartite motif (TRIM) family protein with E3 ubiquitin ligase activity that plays a significant role in the oxidative stress response and tumor suppression. However, the mechanisms regulating TRIM48 expression remain unknown. In this study, we demonstrate that TRIM48 is targeted for ubiquitination-dependent degradation by S-phase kinase-associated protein 1 (Skp1)-Cullin1 (Cul1)-F-box protein (SCF) ubiquitin ligase complex, containing F-box protein 22 (FBXO22) as a substrate recognition subunit. We found that TRIM48 is a rapid turnover protein, as evidenced by the fast and drastic decrease in its protein expression level in the presence of a protein synthesis inhibitor cycloheximide, which was suppressed by knocking down either Skp1, Cul1 or FBXO22. Exogenous FBXO22 expression promoted K48-linked polyubiquitination and degradation of TRIM48. FBXO22 deficiency accelerated oxidative stress-induced activation of apoptosis signal-regulating kinase 1 (ASK1) and cell death, which was reversed by additional TRIM48 knockdown. Collectively, our findings identify the FBXO22 SCF complex as a key negative regulator of TRIM48-driven ASK1-activation and cell death under oxidative stress. The dysregulation of this axis may underlie human-specific pathologies, such as tumorigenesis and oxidative stress-associated disorders, highlighting its potential as a target for novel therapeutic interventions.