Growth of B Cell Receptor Microclusters Is Regulated by PIP2 and PIP3 Equilibrium and Dock2 Recruitment and Activation
Jing Wang,
Liling Xu,
Samina Shaheen,
Sichen Liu,
Wenjie Zheng,
Xiaolin Sun,
Zhanguo Li,
Wanli Liu
Affiliations
Jing Wang
MOE Key Laboratory of Protein Sciences, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, School of Life Sciences, Institute for Immunology, Tsinghua University, Beijing 100084, China
Liling Xu
MOE Key Laboratory of Protein Sciences, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, School of Life Sciences, Institute for Immunology, Tsinghua University, Beijing 100084, China
Samina Shaheen
MOE Key Laboratory of Protein Sciences, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, School of Life Sciences, Institute for Immunology, Tsinghua University, Beijing 100084, China
Sichen Liu
MOE Key Laboratory of Protein Sciences, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, School of Life Sciences, Institute for Immunology, Tsinghua University, Beijing 100084, China
Wenjie Zheng
Department of Rheumatology and Clinical Immunology, Peking Union Medical College Hospital, Peking Union Medical College and Chinese Academy of Medical Sciences, Beijing 100730, China
Xiaolin Sun
Department of Rheumatology and Immunology, Peking University People’s Hospital & Beijing Key Laboratory for Rheumatism Mechanism and Immune Diagnosis (BZ0135), Beijing 100044, China
Zhanguo Li
Department of Rheumatology and Immunology, Peking University People’s Hospital & Beijing Key Laboratory for Rheumatism Mechanism and Immune Diagnosis (BZ0135), Beijing 100044, China
Wanli Liu
MOE Key Laboratory of Protein Sciences, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, School of Life Sciences, Institute for Immunology, Tsinghua University, Beijing 100084, China
The growth of B cell receptor (BCR) microclusters upon antigen stimulation drives B cell activation. Here, we show that PI3K-mediated PIP3 production is required for the growth of BCR microclusters. This growth is likely inhibited by PTEN and dependent on its plasma membrane binding and lipid phosphatase activities. Mechanistically, we find that PIP3-dependent recruitment and activation of a guanine nucleotide exchange factor, Dock2, is required for the sustained growth of BCR microclusters through remodeling of the F-actin cytoskeleton. As a consequence, Dock2 deficiency significantly disrupts the structure of the B cell immunological synapse. Finally, we find that primary B cells from systemic lupus erythematosus (SLE) patients exhibit more prominent BCR and PI3K microclusters than B cells from healthy controls. These results demonstrate the importance of a PI3K- and PTEN-governed PIP2 and PIP3 equilibrium in regulating the activation of B cells through Dock2-controlled growth of BCR microclusters.
