SAG/Rbx2-Dependent Neddylation Regulates T-Cell Responses.

Area of Science:

• Immunology
• Molecular Biology
• Biochemistry

Background:

• Neddylation, a post-translational modification, is essential for cullin ring ligase (CRL) function.
• Sensitive to apoptosis gene (SAG) is a critical E2-adapter component of CRLs, regulating neddylation.
• The role of SAG-dependent neddylation in T-cell immunity remains largely unexplored.

Purpose of the Study:

• To investigate the function of SAG-dependent neddylation in T-cell-mediated immunity.
• To evaluate the therapeutic potential of targeting SAG or neddylation in T-cell immunopathologies.

Main Methods:

• Generated T-cell-specific SAG knockout (KO) mice.
• Utilized the small-molecule neddylation inhibitor MLN4924.
• Assessed T-cell activation, proliferation, and cytokine production in vitro and in vivo.
• Studied allogeneic bone marrow transplantation models to evaluate graft-versus-host disease (GvHD).

Main Results:

• T-cell-specific SAG KO mice exhibited normal T-cell development but impaired T-cell activation, proliferation, and cytokine release upon stimulation.
• Inhibition of SAG or neddylation with MLN4924 reduced T-cell effector functions.
• MLN4924 treatment and SAG deficiency significantly reduced GvHD severity in vivo.
• Mechanistically, SAG deficiency led to increased suppressor of cytokine signaling (SOCS) without affecting NF-κB translocation.

Conclusions:

• SAG is a key regulator of T-cell responses through neddylation.
• Inhibiting neddylation via MLN4924 can mitigate T-cell-mediated immunopathologies like GvHD.
• Targeting SAG or the neddylation pathway presents a promising therapeutic strategy for immune disorders.