STING regulates BCR signaling in normal and malignant B cells
Chih-Hang Anthony Tang, Avery C. Lee, Shiun Chang, Qin Xu, Andong Shao, Yun Lo, Walker T. Spalek, Javier Pinilla‐Ibarz, Juan R. Del Valle, Chih‐Chi Andrew Hu
Abstract
Abstract 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.