STING couples with PI3K to regulate actin reorganization during BCR activation

Abstract

The adaptor protein, STING (stimulator of interferon genes), has been rarely studied in adaptive immunity. We used Sting KO mice and a patient’s mutated STING cells to study the effect of STING deficiency on B cell development, differentiation, and BCR signaling. We found that STING deficiency promotes the differentiation of marginal zone B cells. STING is involved in BCR activation and negatively regulates the activation of CD19 and Btk but positively regulates the activation of SHIP. The activation of WASP and accumulation of F-actin were enhanced in Sting KO B cells upon BCR stimulation. Mechanistically, STING uses PI3K mediated by the CD19-Btk axis as a central hub for controlling the actin remodeling that, in turn, offers feedback to BCR signaling. Overall, our study provides a mechanism of how STING regulates BCR signaling via feedback from actin reorganization, which contributes to positive regulation of STING on the humoral immune response.

Self-DNA Sensing by cGAS-STING and TLR9 in Autoimmunity: Is the Cytoskeleton in Control?

“…Hence, fine-tuned control of STING retention/exit in and from the ER is key to regulate signaling. Intriguingly, it was recently reported that STING controls the accumulation of F-actin via WASP and PI3K in B cells, impacting BCR signaling ( 71 ). There is a strong rationale to predict more connections between actin and STING trafficking.…”

STINGing the Tumor Microenvironment to Promote Therapeutic Tertiary Lymphoid Structure Development

“…Given the pro-apoptotic impact of high-doses of STING agonists on VEC (i.e. vasoablative) and immune cell populations ( 67 , 73 – 76 , 120 , 121 ), but the ability of low-dose regimens to promote VN and enhanced pro-inflammatory immune function in pre-clinical models, it might be anticipated that low-dose protocols will provide optimal immunotherapeutic benefits in these trials. While it is not clear that the formation of TLS represents an exploratory endpoint in these ongoing trial designs, one might expect that low-dose regimens of these next-generation STING agonists will prove effective in inducing de novo development of TLS or expansion of existing TLS within the tumor of treated patients.…”

“…While the exact mechanism underlying this deficiency in CXCL13 production remains unclear, it could relate to the known regulatory action of STING signaling in B cells. For instance, the activation of STING in B cells via genetic engineering to express a constitutively activated form of STING or by treatment of B cells with STING agonists results in endoplasmic reticulum (ER)-associated degradation of membrane-bound immunoglobulin, muted BCR signaling via enhanced SHP1 phosphatase activity and increased rates of B cell apoptosis ( 74 – 76 ).…”

The Trinity of cGAS, TLR9, and ALRs Guardians of the Cellular Galaxy Against Host-Derived Self-DNA

“…The cGAS serves as a potent PRR for the recognition of cytosolic dsDNA in both plasmacytoid DCs (pDCs) and conventional DCs (cDCs), indicating their role in the generation of the potent T-cell-mediated immune response and the B cell-mediated Ab generation ( 20 ). In addition to this, STING also directly impacts adaptive immunity as its deficiency promotes the marginal zone B cell development and differentiation via activating B cell receptor (BCR) signaling ( 98 ). STING positively regulates SHIP-1 (SH2-containing inositol 5′polyphosphatase-1, that is required for B cell tolerance to self-antigens and dampens naïve and low-dose antigen-primed B cells) activation, but negatively regulates CD19 (a 95 kDa type 1 transmembrane protein of immunoglobulin superfamily that establishes a threshold for intrinsic B cell signaling via modulating BCR-dependent and independent signaling) and Bruton’s tyrosine kinase (Btk, essential for B cell development and function of mature B cells downstream to the BCR signaling) ( 98 – 101 ).…”

“…In addition to this, STING also directly impacts adaptive immunity as its deficiency promotes the marginal zone B cell development and differentiation via activating B cell receptor (BCR) signaling ( 98 ). STING positively regulates SHIP-1 (SH2-containing inositol 5′polyphosphatase-1, that is required for B cell tolerance to self-antigens and dampens naïve and low-dose antigen-primed B cells) activation, but negatively regulates CD19 (a 95 kDa type 1 transmembrane protein of immunoglobulin superfamily that establishes a threshold for intrinsic B cell signaling via modulating BCR-dependent and independent signaling) and Bruton’s tyrosine kinase (Btk, essential for B cell development and function of mature B cells downstream to the BCR signaling) ( 98 – 101 ). The BCR activation in the STING -/- B cells increases Wiskott-Aldrich syndrome protein (WASP, which activates downstream to the BCR signaling, links receptor signaling to the actin dynamic through actin-related proteins-2/3 (Arp2/3) complex, and also controls BCR mobility during activation) activation and F-actin accumulation via PI3K used by CD19-Btk axis as a central hub ( 98 , 102 ).…”