Rictor positively regulates B cell receptor signaling by modulating actin reorganization via ezrin

• Published in: PLoS biology 2017-08, Vol.15 (8), p.e2001750-e2001750
• Main Authors: Huang, Lu, Zhang, Yongjie, Xu, Chenguang, Gu, Xiaomei, Niu, Linlin, Wang, Jinzhi, Sun, Xiaoyu, Bai, Xiaoming, Xuan, Xingtian, Li, Qubei, Shi, Chunwei, Yu, Bing, Miller, Heather, Yang, Gangyi, Westerberg, Lisa S, Liu, Wanli, Song, Wenxia, Zhao, Xiaodong, Liu, Chaohong
• Format: Article
• Language: English
• Subjects: Actin; Actins - metabolism; Agammaglobulinaemia Tyrosine Kinase; Animals; Antigens; B cells; B-cell receptor; B-Lymphocytes - metabolism; Biology; Biology and Life Sciences; Bone marrow; Bridged Bicyclo Compounds, Heterocyclic; Carrier Proteins - metabolism; Cell activation; Cell differentiation; Cell Membrane - metabolism; Cellular signal transduction; Child development; Children & youth; Clustering; Collaboration; Cytoskeletal Proteins - metabolism; Dephosphorylation; Differentiation (biology); Education; Ezrin; Hospitals; Immune response; Immune response (humoral); Immune system; Immune systems; Immunity, Humoral; Immunology; Infections; Infectious diseases; Inositol; Inositol-1,4,5-trisphosphate 5-phosphatase; Kinases; Laboratories; Life sciences; Lymphocytes; Lymphocytes B; Lymphocytes T; Machinery; Machinery and equipment; Male; Medical diagnosis; Medicin och hälsovetenskap; Medicine and Health Sciences; Metabolism; Mice; Mice, Inbred C57BL; Mice, Knockout; myo-Inositol-1 (or 4)-monophosphatase; Observations; Pediatrics; Phosphatidylinositol-3,4,5-Trisphosphate 5-Phosphatases - metabolism; Physiological aspects; Polymerization; Protein-tyrosine kinase; Protein-Tyrosine Kinases - metabolism; Protein-tyrosine-phosphatase; Proteins; Rapamycin; Rapamycin-Insensitive Companion of mTOR Protein; Research and Analysis Methods; Research centers; Rodents; Stimulation; Supervision; T cell receptors; Thiazolidines; TOR protein; Tyrosine
• ISSN: 1545-7885; 1544-9173; 1545-7885
• DOI: 10.1371/journal.pbio.2001750

As the central hub of the metabolism machinery, the mammalian target of rapamycin complex 2 (mTORC2) has been well studied in lymphocytes. As an obligatory component of mTORC2, the role of Rictor in T cells is well established. However, the role of Rictor in B cells still remains elusive. Rictor is involved in B cell development, especially the peripheral development. However, the role of Rictor on B cell receptor (BCR) signaling as well as the underlying cellular and molecular mechanism is still unknown. This study used B cell-specfic Rictor knockout (KO) mice to investigate how Rictor regulates BCR signaling. We found that the key positive and negative BCR signaling molecules, phosphorylated Brutons tyrosine kinase (pBtk) and phosphorylated SH2-containing inositol phosphatase (pSHIP), are reduced and enhanced, respectively, in Rictor KO B cells. This suggests that Rictor positively regulates the early events of BCR signaling. We found that the cellular filamentous actin (F-actin) is drastically increased in Rictor KO B cells after BCR stimulation through dysregulating the dephosphorylation of ezrin. The high actin-ezrin intensity area restricts the lateral movement of BCRs upon stimulation, consequently reducing BCR clustering and BCR signaling. The reduction in the initiation of BCR signaling caused by actin alteration is associated with a decreased humoral immune response in Rictor KO mice. The inhibition of actin polymerization with latrunculin in Rictor KO B cells rescues the defects of BCR signaling and B cell differentiation. Overall, our study provides a new pathway linking cell metablism to BCR activation, in which Rictor regulates BCR signaling via actin reorganization.