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

TL;DR

This study shows that FBXO22 helps control cell death caused by oxidative stress by breaking down a protein called TRIM48.

Contribution

The study identifies FBXO22 as a novel regulator of TRIM48 degradation and its role in suppressing ASK1 activation and cell death.

Findings

TRIM48 is rapidly degraded via ubiquitination by the SCF complex containing FBXO22.

FBXO22 deficiency increases oxidative stress-induced ASK1 activation and cell death.

TRIM48 knockdown reverses the cell death caused by FBXO22 deficiency.

Abstract

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.

Figures