Cytoskeletal Protein 4.1R Inhibits BCR-Mediated B-Cell Activation by Restraining AKT1 Phosphorylation

Area of Science:

• Immunology
• Molecular Biology
• Cell Signaling

Background:

• B-cell receptor (BCR) signaling is crucial for B-cell responses and involves cytoskeletal protein rearrangement.
• Cytoskeletal protein 4.1R is implicated in immune function, but its role in BCR-mediated B-cell activation is unclear.

Purpose of the Study:

• To investigate the specific role of 4.1R in BCR-mediated B-cell activation.
• To characterize the functional contribution of 4.1R to B-cell biology using transcriptomic and phosphoproteomic analyses.

Main Methods:

• Single-cell RNA sequencing (scRNA-seq) of splenic B cells from wild-type (WT) and 4.1R-knockout (4.1R-KO) mice.
• Ex vivo stimulation of primary B cells with anti-IgM.
• Unbiased phosphoproteomic profiling and co-immunoprecipitation assays.

Main Results:

• 4.1R-KO B cells exhibited overactivation, hyperproliferation, and enhanced antibody secretion upon anti-IgM stimulation.
• Sustained AKT1 phosphorylation was identified as a key feature in 4.1R-KO B cells.
• 4.1R interacts with CD19 at the plasma membrane, and its loss disrupts this interaction, leading to amplified AKT1 activation.

Conclusions:

• 4.1R acts as a novel negative regulator of BCR signaling.
• 4.1R constrains AKT1 activation by interacting with CD19.
• Dysregulation of 4.1R impacts B-cell activation and antibody secretion.