Regulation of T cell function by the ubiquitin-specific protease USP9X via modulating the Carma1-Bcl10-Malt1 complex

Area of Science:

• Immunology
• Molecular Biology
• Cell Biology

Background:

• The ubiquitin system is vital for immune regulation.
• Ubiquitin-specific proteases (USPs) roles in deubiquitination are not fully understood.
• USP9X's function in T-cells requires further elucidation.

Purpose of the Study:

• To investigate the role of USP9X in T-cell function and immune regulation.
• To elucidate the mechanism by which USP9X affects T-cell receptor signaling.
• To determine USP9X's impact on T-cell proliferation, differentiation, and cytokine production.

Main Methods:

• In vivo knockdown of USP9X in mice.
• Analysis of naïve CD4(+) T cells from chimeric mice.
• In vitro and in vivo adoptive transfer experiments.
• Assessment of T-cell receptor signaling and NF-κB activation.
• Co-immunoprecipitation to study protein interactions within the CBM complex.

Main Results:

• USP9X knockdown significantly reduced T-cell proliferation in vivo.
• USP9X-deficient T cells showed impaired cytokine production and T helper cell differentiation.
• USP9X silencing diminished T-cell receptor signaling-induced NF-κB activation.
• USP9X interacts with Bcl10 in the Carma1-Bcl10-Malt1 (CBM) complex.
• USP9X removes ubiquitin chains from Bcl10, promoting CBM complex formation.

Conclusions:

• USP9X is a critical positive regulator of T-cell receptor signaling.
• USP9X is essential for T-cell function, including proliferation and differentiation.
• USP9X modulates T-cell immunity by regulating CBM complex assembly via Bcl10 deubiquitination.