BAFF activation of the ERK5 MAP kinase pathway regulates B cell survival
journal contributionposted on 2020-08-20, 13:48 authored by Emilie Jacque, Edina Schweighoffer, Victor LJ Tybulewicz, Steven C Ley
B cell activating factor (BAFF) stimulation of the BAFF receptor (BAFF-R) is essential for the homeostatic survival of mature B cells. Earlier in vitro experiments with inhibitors that block MEK 1 and 2 suggested that activation of ERK 1 and 2 MAP kinases is required for BAFF-R to promote B cell survival. However, these inhibitors are now known to also inhibit MEK5, which activates the related MAP kinase ERK5. In the present study, we demonstrated that BAFF-induced B cell survival was actually independent of ERK1/2 activation but required ERK5 activation. Consistent with this, we showed that conditional deletion of ERK5 in B cells led to a pronounced global reduction in mature B2 B cell numbers, which correlated with impaired survival of ERK5-deficient B cells after BAFF stimulation. ERK5 was required for optimal BAFF up-regulation of Mcl1 and Bcl2a1, which are prosurvival members of the Bcl-2 family. However, ERK5 deficiency did not alter BAFF activation of the PI3-kinase-Akt or NF-κB signaling pathways, which are also important for BAFF to promote mature B cell survival. Our study reveals a critical role for the MEK5-ERK5 MAP kinase signaling pathway in BAFF-induced mature B cell survival and homeostatic maintenance of B2 cell numbers.
AnimalsB-Cell Activating FactorB-LymphocytesBone Marrow CellsCell SurvivalEnzyme ActivationExtracellular Signal-Regulated MAP KinasesFemaleFlow CytometryGene DeletionGene Expression Regulation, EnzymologicMAP Kinase Kinase 5MAP Kinase Signaling SystemMaleMiceMice, Inbred C57BLMice, TransgenicMinor Histocompatibility AntigensMitogen-Activated Protein Kinase 7Myeloid Cell Leukemia Sequence 1 ProteinPhosphatidylinositol 3-KinasesProto-Oncogene Proteins c-aktProto-Oncogene Proteins c-bcl-2Signal TransductionUp-RegulationTybulewicz U117527252Ley U117584209BRF-ackFC-ackRI-ack11 Medical and Health SciencesImmunology