STING is an endoplasmic reticulum (ER)-resident protein critical for sensing cytoplasmic DNA and promoting the production of type I interferons; however, the role of STING in B cell receptor (BCR) signaling remains unclear. We generated STING V154M knock-in mice and showed that B cells carrying constitutively activated STING specifically degraded membrane-bound IgM, Igα, and Igβ via SEL1L/HRD1-mediated ER-associated degradation (ERAD). B cells with activated STING were thus less capable of responding to BCR activation by phosphorylating Igα and Syk than those without activated STING. When immunized with T-independent antigens, STING V154M mice produced significantly fewer antigen-specific plasma cells and antibodies than immunized wild-type (WT) mice. We further generated B cell-specific STING^KO mice and showed that STING^KO B cells indeed responded to activation by transducing stronger BCR signals than their STING-proficient counterparts. When B cell-specific STING^KO mice were T-independently immunized, they produced significantly more antigen-specific plasma cells and antibodies than immunized STING^WT mice. Since both human and mouse IGHV-unmutated malignant chronic lymphocytic leukemia (CLL) cells downregulated the expression of STING, we explored whether STING downregulation could contribute to the well-established robust BCR signaling phenotype in malignant CLL cells. We generated a STING-deficient CLL mouse model and showed that STING-deficient CLL cells were indeed more responsive to BCR activation than their STING-proficient counterparts. These results revealed a novel B cell-intrinsic role of STING in negatively regulating BCR signaling in both normal and malignant B cells.

STING 是一种内质网 (ER) 驻留蛋白，对于感知细胞质 DNA 和促进 I 型干扰素的产生至关重要；然而，STING 在 B 细胞受体 (BCR) 信号传导中的作用仍不清楚。我们生成了 STING V154M 敲入小鼠，并显示携带组成型激活的 STING 的 B 细胞通过 SEL1L/HRD1 介导的 ER 相关降解 (ERAD) 特异性降解膜结合的 IgM、Igα 和 Igβ。因此，与未激活 STING 的 B 细胞相比，具有激活 STING 的 B 细胞通过磷酸化 Igα 和 Syk 对 BCR 激活的反应能力较低。当用 T 非依赖性抗原免疫时，STING V154M 小鼠产生的抗原特异性浆细胞和抗体明显少于免疫的野生型 (WT) 小鼠。我们进一步生成了 B 细胞特异性 STING ^KO小鼠并表明 STING ^KO B 细胞确实通过转导比 STING 熟练对应物更强的 BCR 信号来响应激活。当 B 细胞特异性 STING ^KO小鼠进行 T 独立免疫时，它们产生的抗原特异性浆细胞和抗体明显多于免疫 STING ^WT老鼠。由于人和小鼠 IGHV 未突变的恶性慢性淋巴细胞白血病 (CLL) 细胞都下调了 STING 的表达，我们探讨了 STING 下调是否有助于恶性 CLL 细胞中成熟的稳健 BCR 信号传导表型。我们生成了一个 STING 缺陷 CLL 小鼠模型，并表明 STING 缺陷 CLL 细胞确实比 STING 熟练对应细胞对 BCR 激活更敏感。这些结果揭示了 STING 在负调节正常和恶性 B 细胞中的 BCR 信号传导中的一种新的 B 细胞内在作用。