STING regulates BCR signaling in normal and malignant B cells

Area of Science:

• Immunology
• Cell Biology
• Molecular Biology

Background:

• STING (stimulator of interferon genes) is crucial for innate immunity, sensing DNA in the cytoplasm.
• Its role in B cell receptor (BCR) signaling, a key pathway for B cell activation and function, was previously unknown.

Purpose of the Study:

• To investigate the function of STING in B cell receptor (BCR) signaling.
• To determine STING's role in both normal B cells and malignant chronic lymphocytic leukemia (CLL) cells.

Main Methods:

• Generated STING V154M knock-in mice with constitutively activated STING.
• Created B cell-specific STING knockout (STING^KO) mice.
• Developed a STING-deficient CLL mouse model.
• Utilized SEL1L/HRD1-mediated ER-associated degradation (ERAD) pathway analysis.

Main Results:

• Activated STING in B cells promotes degradation of IgM, Igα, and Igβ via ERAD, impairing BCR signaling.
• STING-deficient B cells exhibit enhanced BCR signaling and antibody production upon T-independent antigen immunization.
• STING deficiency in CLL cells enhances their responsiveness to BCR activation, mirroring the phenotype of malignant CLL cells.

Conclusions:

• STING acts as a negative regulator of BCR signaling in a B cell-intrinsic manner.
• STING downregulation may contribute to the enhanced BCR signaling observed in malignant CLL cells.
• This study uncovers a novel function of STING in immune regulation and B cell malignancies.