title: The kinase TBK1 controls IgA class switching by negatively regulating noncanonical NF-κB signaling.
abstract: Immunoglobulin class switching is crucial for the generation of antibody diversity in humoral immunity and, when deregulated, also has severe pathological consequences. How the magnitude of immunoglobulin isotype switching is controlled is still poorly understood. Here we identify the kinase TBK1 as a pivotal negative regulator of class switching to the immunoglobulin A (IgA) isotype. B cell-specific ablation of TBK1 in mice resulted in uncontrolled production of IgA and the development of nephropathy-like disease signs. TBK1 negatively regulated IgA class switching by attenuating noncanonical signaling via the transcription factor NF-κB, an action that involved TBK1-mediated phosphorylation and subsequent degradation of the NF-κB-inducing kinase NIK. Our findings establish TBK1 as a pivotal negative regulator of the noncanonical NF-κB pathway and identify a unique mechanism that controls IgA production.
authors.affiliation: Department of Immunology, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA.
authors.forename: Jin
authors.initials: J
authors.lastname: Jin
authors.forename: Yichuan
authors.initials: Y
authors.lastname: Xiao
authors.forename: Jae-Hoon
authors.initials: JH
authors.lastname: Chang
authors.forename: Jiayi
authors.initials: J
authors.lastname: Yu
authors.forename: Hongbo
authors.initials: H
authors.lastname: Hu
authors.forename: Robyn
authors.initials: R
authors.lastname: Starr
authors.forename: George C
authors.initials: GC
authors.lastname: Brittain
authors.forename: Mikyoung
authors.initials: M
authors.lastname: Chang
authors.forename: Xuhong
authors.initials: X
authors.lastname: Cheng
authors.forename: Shao-Cong
authors.initials: SC
authors.lastname: Sun
mesh_terms: D000818:Animals; D001402:B-Lymphocytes / Q000276:immunology / Q000473:pathology; D017353:Gene Deletion; D005786:Gene Expression Regulation / Q000276:immunology; D005922:Glomerulonephritis, IGA / Q000235:genetics* / Q000276:immunology / Q000473:pathology; D007070:Immunoglobulin A / Q000235:genetics* / Q000276:immunology; D017578:Immunoglobulin Class Switching / Q000235:genetics* / Q000276:immunology; D051379:Mice; D018345:Mice, Knockout; D016328:NF-kappa B / Q000235:genetics* / Q000276:immunology; D010766:Phosphorylation; D017346:Protein Serine-Threonine Kinases / Q000172:deficiency / Q000235:genetics* / Q000276:immunology / Q000378:metabolism; D059748:Proteolysis; D015398:Signal Transduction; D000097782:NF-kappaB-Inducing Kinase
chemical_list: D007070:Immunoglobulin A; D016328:NF-kappa B; D017346:Protein Serine-Threonine Kinases; D000097782:NF-kappaB-Inducing Kinase; C498588:Tbk1 protein, mouse