STING regulates BCR signaling in normal and malignant B cells

作     者：Chih-Hang Anthony Tang Avery C.Lee Shiun Chang Qin Xu Andong Shao Yun Lo Walker T.Spalek Javier A.Pinilla-lbarz Juan R.Del Valle Chih-Chi Andrew Hu Chih-Hang Anthony Tang;Avery C.Lee;Shiun Chang;Qin Xu;Andong Shao;Yun Lo;Walker T.Spalek;Javier A.Pinilla-lbarz;Juan R.Del Valle;Chih-Chi Andrew Hu

作者机构：The Wistar Institute3601 Spruce StreetPhiladelphiaPA 19104USA Department of Malignant HematologyH.Lee Moffitt Cancer Center&Research InstituteTampaFL 33612USA Department of Chemistry&BiochemistryUniversity of Notre DameNotre DameIN 46556USA 

出 版 物：《Cellular & Molecular Immunology》 (中国免疫学杂志（英文版）)

年 卷 期：2021年第18卷第4期

页      面：1016-1031页

核心收录：

学科分类：1001[医学-基础医学(可授医学、理学学位)] 100102[医学-免疫学] 10[医学] 

基　　金：supported by grants(R01CA163910 and R01CA190860)from the NIH/NCI 

主　　题：STING BCR ER-associated degradation CLL Plasma cells 

摘      要：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 *** generated STING V154M knock-in mice and showed that B cells carrying constitutively activated STING specifically degraded membrane-bound IgM,Ig a 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 *** immunized with T-independent antigens,STING V154M mice produced significantly fewer antigen-specific plasma cells and antibodies than immunized wild-type(WT)*** 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 *** B cell-specific STING^(KO) mice were T-independently immunized,they produced significantly more antigen-specific plasma cells and antibodies than immunized STIN^(WT)*** both human and m ouse 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 *** 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 *** results revealed a novel B cell-intrinsic role of STING in negatively regulating BCR signaling in both normal and malignant B cells.