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Protein kinase 2 (CK2) controls CD4+ T cell effector function in the pathogenesis of colitis.

ABSTRACT: Crohn's disease (CD), one of the major forms of inflammatory bowel disease (IBD), is characterized by chronic inflammation of the gastrointestinal tract and associated with aberrant CD4+ T-helper type 1 (Th1) and Th17 responses. Protein kinase 2 (CK2) is a conserved serine-threonine kinase involved in signal transduction pathways, which regulate immune responses. CK2 promotes Th17 cell differentiation and suppresses the generation of Foxp3+ regulatory T cells. The function of CK2 in CD4+ T cells during the pathogenesis of CD is unknown. We utilized the T cell-induced colitis model, transferring CD45RBhi-naive CD4+ T cells from CK2?fl/fl controls and CK2?fl/fldLck-Cre mice into Rag1-/- mice. CD4+ T cells from CK2?fl/fldLck-Cre mice failed to induce wasting disease and significant intestinal inflammation, which was associated with decreased interleukin-17A-positive (IL-17A+), interferon-?-positive (IFN-?+), and double-positive IL-17A+IFN-?+ CD4+ T cells in the spleen and colon. We determined that CK2? regulates CD4+ T cell proliferation through a cell-intrinsic manner. CK2? is also important in controlling CD4+ T cell responses by regulating NFAT2, which is vital for T cell activation and proliferation. Our findings indicate that CK2? contributes to the pathogenesis of colitis by promoting CD4+ T cell proliferation and Th1 and Th17 responses, and that targeting CK2 may be a novel therapeutic treatment for patients with CD.

SUBMITTER: Yang W

PROVIDER: S-EPMC7382987 | biostudies-literature | 2020 Sep

REPOSITORIES: biostudies-literature

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Protein kinase 2 (CK2) controls CD4+ T cell effector function in the pathogenesis of colitis.

Yang Wei W Gibson Sara A SA Yan Zhaoqi Z Wei Hairong H Tao Jiahui J Sha Bingdong B Qin Hongwei H Benveniste Etty N EN

Mucosal immunology 20200127 5

Crohn's disease (CD), one of the major forms of inflammatory bowel disease (IBD), is characterized by chronic inflammation of the gastrointestinal tract and associated with aberrant CD4+ T-helper type 1 (Th1) and Th17 responses. Protein kinase 2 (CK2) is a conserved serine-threonine kinase involved in signal transduction pathways, which regulate immune responses. CK2 promotes Th17 cell differentiation and suppresses the generation of Foxp3+ regulatory T cells. The function ...[more]

PMID: 31988467

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Project description:In yeast, Tom22, the central component of the TOMM (translocase of outer mitochondrial membrane) receptor complex, is responsible for the recognition and translocation of synthesized mitochondrial precursor proteins, and its protein kinase CK2-dependent phosphorylation is mandatory for TOMM complex biogenesis and proper mitochondrial protein import. In mammals, the biological function of protein kinase CSNK2/CK2 remains vastly elusive and it is unknown whether CSNK2-dependent phosphorylation of TOMM protein subunits has a similar role as that in yeast. To address this issue, we used a skeletal muscle-specific Csnk2b/Ck2?-conditional knockout (cKO) mouse model. Phenotypically, these skeletal muscle Csnk2b cKO mice showed reduced muscle strength and abnormal metabolic activity of mainly oxidative muscle fibers, which point towards mitochondrial dysfunction. Enzymatically, active muscle lysates from skeletal muscle Csnk2b cKO mice phosphorylate murine TOMM22, the mammalian ortholog of yeast Tom22, to a lower extent than lysates prepared from controls. Mechanistically, CSNK2-mediated phosphorylation of TOMM22 changes its binding affinity for mitochondrial precursor proteins. However, in contrast to yeast, mitochondrial protein import seems not to be affected in vitro using mitochondria isolated from muscles of skeletal muscle Csnk2b cKO mice. PINK1, a mitochondrial health sensor that undergoes constitutive import under physiological conditions, accumulates within skeletal muscle Csnk2b cKO fibers and labels abnormal mitochondria for removal by mitophagy as demonstrated by the appearance of mitochondria-containing autophagosomes through electron microscopy. Mitophagy can be normalized by either introduction of a phosphomimetic TOMM22 mutant in cultured myotubes, or by in vivo electroporation of phosphomimetic Tomm22 into muscles of mice. Importantly, transfection of the phosphomimetic Tomm22 mutant in muscle cells with ablated Csnk2b restored their oxygen consumption rate comparable to wild-type levels. In sum, our data show that mammalian CSNK2-dependent phosphorylation of TOMM22 is a critical switch for mitophagy and reveal CSNK2-dependent physiological implications on metabolism, muscle integrity and behavior.

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Protein kinase 2 (CK2) controls CD4+ T cell effector function in the pathogenesis of colitis.

Publications

Protein kinase 2 (CK2) controls CD4<sup>+</sup> T cell effector function in the pathogenesis of colitis.

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