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 A. Pinilla-Ibarz, Juan R. Del Valle, Chih Chi Andrew Hu

Research output: Contribution to journalArticlepeer-review

2 Scopus citations

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 STINGKO mice and showed that STINGKO B cells indeed responded to activation by transducing stronger BCR signals than their STING-proficient counterparts. When B cell-specific STINGKO mice were T-independently immunized, they produced significantly more antigen-specific plasma cells and antibodies than immunized STINGWT 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.

Original languageEnglish (US)
Pages (from-to)1016-1031
Number of pages16
JournalCellular and Molecular Immunology
Volume18
Issue number4
DOIs
StatePublished - Apr 2021

Keywords

  • BCR
  • CLL
  • ER-associated degradation
  • Plasma cells
  • STING

ASJC Scopus subject areas

  • Immunology and Allergy
  • Immunology
  • Infectious Diseases

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