USP15 potentiates NF-κB activation by differentially stabilizing TAB2 and TAB3.

Area of Science:

• Molecular Biology
• Cellular Biology
• Biochemistry

Background:

• Nuclear factor-κB (NF-κB) activation is crucial for inflammation, immunity, and cancer.
• Tumor necrosis factor α (TNFα) and interleukin 1β (IL-1β) are key inducers of NF-κB signaling.
• Deubiquitinating enzymes (DUBs) regulate protein stability and signaling pathways.

Purpose of the Study:

• To identify novel regulators of TNFα- and IL-1β-induced NF-κB activation.
• To elucidate the mechanism by which ubiquitin-specific protease 15 (USP15) affects NF-κB signaling.
• To investigate the role of USP15 in maintaining the stability of TAK1-binding proteins (TAB2/3).

Main Methods:

• Overexpression and knockdown of USP15 in cellular models.
• Analysis of NF-κB activation and downstream gene transcription.
• Co-immunoprecipitation assays to study protein interactions.
• Investigation of ubiquitination, proteolysis, and autophagic degradation pathways.

Main Results:

• USP15 was identified as a positive regulator of TNFα- and IL-1β-induced NF-κB activation.
• USP15 overexpression potentiated NF-κB activation, while knockdown inhibited it.
• USP15 stabilized TAB2/3 by inhibiting their proteolysis through deubiquitination-dependent and -independent mechanisms.
• USP15 prevented TAB2 degradation via lysosomes and TAB3 degradation via autophagy.

Conclusions:

• USP15 is a novel positive regulator of NF-κB activation.
• USP15 stabilizes TAB2/3 through multiple pathways, enhancing NF-κB signaling.
• Understanding USP15's role provides insights into inflammatory and immune responses and cancer development.