Preventing abnormal NF-κB activation and autoimmunity by Otub1-mediated p100 stabilization

Area of Science:

• Immunology
• Molecular Biology
• Cell Biology

Background:

• Nuclear factor kappa B (NF-κB) transcription factors regulate immune responses via canonical and noncanonical pathways.
• p100 protein processing and degradation are key events in NF-κB pathway activation.

Purpose of the Study:

• To investigate the role of the deubiquitinase Otub1 in regulating p100 stability and NF-κB pathway activation.
• To determine the impact of Otub1 deficiency on B-cell function and autoimmunity.

Main Methods:

• Studied p100 protein stability and NF-κB activation in Otub1-deficient cells.
• Utilized B-cell-conditional deletion of Otub1 in a mouse model.
• Analyzed B-cell phenotypes, antibody production, and cytokine profiles (IL-6).

Main Results:

• Otub1 deficiency promotes p100 processing and noncanonical NF-κB activation.
• Otub1 deficiency causes steady-state p100 degradation, leading to aberrant canonical NF-κB activation.
• B-cell-specific Otub1 deletion induced B-cell hyperplasia, autoantibody production, and lupus-like autoimmunity.
• Otub1-deficient B cells overproduced IL-6, contributing to autoimmune pathology.

Conclusions:

• Otub1 is a critical regulator of p100 stability, thereby controlling NF-κB pathway activation.
• Otub1-dependent p100 stabilization is essential for preventing aberrant NF-κB signaling and autoimmunity.
• Otub1 deficiency in B cells triggers autoimmune responses through dysregulated NF-κB signaling and IL-6 overproduction.