OTUB1 Modulates Ferroptosis by Regulating SLC7A11 Ubiquitination in Pancreatic β-Cells

Area of Science:

• Cell Biology
• Metabolic Diseases
• Biochemistry

Background:

• Ferroptosis, an iron-dependent cell death, contributes to pancreatic beta-cell dysfunction in diabetes.
• Understanding the molecular mechanisms of ferroptosis in beta cells is crucial for developing diabetes therapies.

Purpose of the Study:

• To investigate how 2-deoxy-d-ribose (dRib) induces ferroptosis in pancreatic beta cells.
• To identify the regulatory role of the OTUB1-SLC7A11 axis in dRib-induced beta-cell ferroptosis.

Main Methods:

• Utilized rat insulinoma-derived RIN5mF cells and isolated rat islets.
• Assessed cystine uptake, glutathione (GSH) levels, lipid peroxidation, reactive oxygen species (ROS), and protein ubiquitination.
• Performed Western blotting, quantitative real-time PCR, and transmission electron microscopy.
• Investigated the effects of OTUB1 and SLC7A11 overexpression.

Main Results:

• dRib exposure impaired cystine uptake via system χc-, depleted GSH, and increased lipid peroxidation and ROS.
• SLC7A11 protein levels decreased due to enhanced ubiquitination and proteasomal degradation, despite increased mRNA.
• dRib suppressed OTUB1 expression, leading to SLC7A11 destabilization and promoting ferroptosis.
• Overexpression of OTUB1 or SLC7A11 rescued cystine transport, replenished GSH, reduced lipid ROS, and prevented cell death.
• Mitochondrial morphology changes consistent with ferroptosis were observed.

Conclusions:

• The OTUB1-SLC7A11 axis is a critical regulator of ferroptosis in pancreatic beta cells.
• Loss of OTUB1 promotes beta-cell ferroptosis by destabilizing SLC7A11.
• Targeting the OTUB1-SLC7A11 pathway offers a potential therapeutic strategy for diabetes by preserving beta-cell survival.