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AKT2 deficiency impairs formation of the BCR signalosome.

ABSTRACT: BACKGROUND:AKT2 is one of the key molecules that involves in the insulin-induced signaling and the development of cancer. In B cells, the function of AKT2 is unclear. METHODS:In this study, we used AKT2 knockout mice model to study the role of AKT2 in BCR signaling and B cell differentiation. RESULTS:AKT2 promotes the early activation of B cells by enhancing the BCR signaling and actin remodeling. B cells from AKT2 KO mice exhibited defective spreading and BCR clustering upon stimulation in vitro. Disruption of Btk-mediated signaling caused the impaired differentiation of germinal center B cells, and the serum levels of both sepecific IgM and IgG were decreased in the immunized AKT2 KO mice. In addition, the actin remodeling was affected due to the decreased level of the activation of WASP, the actin polymerization regulator, in AKT2 KO mice as well. As a crucial regulator of both BCR signaling and actin remodeling during early activation of B cells, the phosphorylation of CD19 was decreased in the AKT2 absent B cells, while the transcription level was normal. CONCLUSIONS:AKT2 involves in the humoral responses, and promotes the BCR signaling and actin remodeling to enhance the activation of B cells via regulating CD19 phosphorylation. Video Abstract.

SUBMITTER: Du Z

PROVIDER: S-EPMC7133013 | biostudies-literature | 2020 Apr

REPOSITORIES: biostudies-literature

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AKT2 deficiency impairs formation of the BCR signalosome.

Du Zuochen Z Yang Di D Zhang Yongjie Y Xuan Xingtian X Li Han H Hu Leling L Ruan Changshun C Li Liling L Chen Anwei A Deng Liang L Chen Yan Y Xie Jingwen J Westerberg Lisa S LS Huang Lu L Liu Chaohong C

Cell communication and signaling : CCS 20200406 1

<h4>Background</h4>AKT2 is one of the key molecules that involves in the insulin-induced signaling and the development of cancer. In B cells, the function of AKT2 is unclear.<h4>Methods</h4>In this study, we used AKT2 knockout mice model to study the role of AKT2 in BCR signaling and B cell differentiation.<h4>Results</h4>AKT2 promotes the early activation of B cells by enhancing the BCR signaling and actin remodeling. B cells from AKT2 KO mice exhibited defective spreading and BCR clustering up ...[more]

PMID: 32252758

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Project description:Acute oligodendrocyte (OL) death after traumatic spinal cord injury (SCI) is followed by robust neuron-glial antigen 2 (NG2)-positive OL progenitor proliferation and differentiation into new OLs. Inflammatory mediators are prevalent during both phases and can influence the fate of NG2 cells and OLs. Specifically, toll-like receptor (TLR) 4 signaling induces OL genesis in the naive spinal cord, and lack of TLR4 signaling impairs white matter sparing and functional recovery after SCI. Therefore, we hypothesized that TLR4 signaling may regulate oligodendrogenesis after SCI. C3H/HeJ (TLR4-deficient) and control (C3H/HeOuJ) mice received a moderate midthoracic spinal contusion. TLR4-deficient mice showed worse functional recovery and reduced OL numbers compared with controls at 24 h after injury through chronic time points. Acute OL loss was accompanied by reduced ferritin expression, which is regulated by TLR4 and needed for effective iron storage. TLR4-deficient injured spinal cords also displayed features consistent with reduced OL genesis, including reduced NG2 expression, fewer BrdU-positive OLs, altered BMP4 signaling and inhibitor of differentiation 4 (ID4) expression, and delayed myelin phagocytosis. Expression of several factors, including IGF-1, FGF2, IL-1?, and PDGF-A, was altered in TLR4-deficient injured spinal cords compared with wild types. Together, these data show that TLR4 signaling after SCI is important for OL lineage cell sparing and replacement, as well as in regulating cytokine and growth factor expression. These results highlight new roles for TLR4 in endogenous SCI repair and emphasize that altering the function of a single immune-related receptor can dramatically change the reparative responses of multiple cellular constituents in the injured CNS milieu.Myelinating cells of the CNS [oligodendrocytes (OLs)] are killed for several weeks after traumatic spinal cord injury (SCI), but they are replaced by resident progenitor cells. How the concurrent inflammatory signaling affects this endogenous reparative response is unclear. Here, we provide evidence that immune receptor toll-like receptor 4 (TLR4) supports OL lineage cell sparing, long-term OL and OL progenitor replacement, and chronic functional recovery. We show that TLR4 signaling is essential for acute iron storage, regulating cytokine and growth factor expression, and efficient myelin debris clearance, all of which influence OL replacement. Importantly, the current study reveals that a single immune receptor is essential for repair responses after SCI, and the potential mechanisms of this beneficial effect likely change over time after injury.

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AKT2 deficiency impairs formation of the BCR signalosome.

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AKT2 deficiency impairs formation of the BCR signalosome.

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